ORCID Profile
0000-0002-8224-3203
Current Organisation
University of California, San Diego
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Publisher: Wiley
Date: 09-10-2009
Publisher: American Physiological Society
Date: 06-2019
DOI: 10.1152/AJPENDO.00497.2018
Abstract: Akt is a critical mediator of insulin-stimulated glucose uptake in skeletal muscle. The acetyltransferases, E1A binding protein p300 (p300) and cAMP response element-binding protein binding protein (CBP) are phosphorylated and activated by Akt, and p300/CBP can acetylate and inactivate Akt, thus giving rise to a possible Akt-p300/CBP axis. Our objective was to determine the importance of p300 and CBP to skeletal muscle insulin sensitivity. We used Cre-LoxP methodology to generate mice with germline [muscle creatine kinase promoter (P-MCK and C-MCK)] or inducible [tamoxifen-activated, human skeletal actin promoter (P-iHSA and C-iHSA)] knockout of p300 or CBP. A subset of P-MCK and C-MCK mice were switched to a calorie-restriction diet (60% of ad libitum intake) or high-fat diet at 10 wk of age. For P-iHSA and C-iHSA mice, knockout was induced at 10 wk of age. At 13–15 wk of age, we measured whole-body energy expenditure, oral glucose tolerance, and/or ex vivo skeletal muscle insulin sensitivity. Although p300 and CBP protein abundance and mRNA expression were reduced 55%–90% in p300 and CBP knockout mice, there were no genotype differences in energy expenditure or fasting glucose and insulin concentrations. Moreover, neither loss of p300 or CBP impacted oral glucose tolerance or skeletal muscle insulin sensitivity, nor did their loss impact alterations in these parameters in response to a calorie restriction or high-fat diet. Muscle-specific loss of either p300 or CBP, be it germline or in adulthood, does not impact energy expenditure, glucose tolerance, or skeletal muscle insulin action.
Publisher: JMIR Publications Inc.
Date: 13-05-2021
DOI: 10.2196/28684
Abstract: Many older adults spend the majority of their waking hours sitting, which increases their risk of chronic diseases. Given the challenges that many older adults face when engaging in moderate-to-vigorous physical activity, understanding the health benefits of decreasing sitting time and increasing the number of sit-to-stand transitions is needed to address this growing public health concern. The aim of this 3-arm randomized controlled trial is to investigate how changes in sitting time and brief sit-to-stand transitions impact biomarkers of healthy aging and physical, emotional, and cognitive functioning compared with a healthy attention control arm. Sedentary and postmenopausal women (N=405) will be recruited and randomly assigned to 1 of the 3 study conditions for 3 months: healthy living attention control (Healthy Living), reduce sitting time (Reduce Sitting), and increase sit-to-stand transitions (Increase Transitions). Assessments conducted at baseline and 3 months included fasting blood draw, blood pressure, anthropometric measurements, physical functioning, cognitive testing, and 7 days of a thigh-worn accelerometer (activPAL) and a hip-worn accelerometer (ActiGraph). Blood-based biomarkers of healthy aging included those associated with glycemic control (glycated hemoglobin, fasting plasma insulin and glucose, and homeostatic model assessment of insulin resistance). Recruitment began in May 2018. The intervention is ongoing, with data collection expected to continue through the end of 2022. The Rise for Health study is designed to test whether 2 different approaches to interrupting sitting time can improve healthy aging in postmenopausal women. Results from this study may inform the development of sedentary behavior guidelines and interventions to reduce sitting time in older adults. ClinicalTrials.gov NCT03473145 t2/show/NCT03473145 DERR1-10.2196/28684
Publisher: Springer Science and Business Media LLC
Date: 08-03-2021
Publisher: Public Library of Science (PLoS)
Date: 30-11-2017
Publisher: Wiley
Date: 19-10-2015
DOI: 10.1096/FJ.15-276360
Publisher: American Physiological Society
Date: 08-2006
DOI: 10.1152/AJPENDO.00051.2006
Abstract: Although the increase in fatty acid oxidation after endurance exercise training has been linked with improvements in insulin sensitivity and overall metabolic health, the mechanisms responsible for increasing fatty acid oxidation after exercise training are not completely understood. The primary aim of this study was to determine the effect of adding endurance exercise training to a weight loss program on fat oxidation and the colocalization of the fatty acid translocase FAT/CD36 with carnitine palmitoyltransferase I (CPT I) in human skeletal muscle. We measured postabsorptive fat oxidation and acquired a muscle s le from abdominally obese women before and after 12% body weight loss through either dietary intervention with endurance exercise training (EX + DIET) or dietary intervention without endurance exercise training (DIET). Immunoprecipitation techniques were used on these muscle s les to determine whether the association between FAT/CD36 and CPT I is altered after DIET and/or EX + DIET. FAT/CD36 was found to coimmunoprecipitate with CPT I, and the amount of FAT/CD36 that coimmunoprecipitated with CPT I increased by ∼25% after EX + DIET ( P 0.005) but was unchanged after DIET. In addition, the increase in the amount of FAT/CD36 that coimmunoprecipitated with CPT I in EX + DIET was strongly correlated with the increase in whole body fat oxidation ( R 2 = 0.857, P 0.003). In conclusion, the findings from this study indicate that exercise training alters the localization of FAT/CD36 and increases its association with CPT I, which may help augment fat oxidation.
Publisher: Elsevier BV
Date: 08-2015
Publisher: Springer Science and Business Media LLC
Date: 27-03-2017
Publisher: American Diabetes Association
Date: 17-01-2013
DOI: 10.2337/DB12-0686
Abstract: Dysregulated lipid metabolism and inflammation are linked to the development of insulin resistance in obesity, and the intracellular accumulation of the sphingolipid ceramide has been implicated in these processes. Here, we explored the role of circulating ceramide on the pathogenesis of insulin resistance. Ceramide transported in LDL is elevated in the plasma of obese patients with type 2 diabetes and correlated with insulin resistance but not with the degree of obesity. Treating cultured myotubes with LDL containing ceramide promoted ceramide accrual in cells and was accompanied by reduced insulin-stimulated glucose uptake, Akt phosphorylation, and GLUT4 translocation compared with LDL deficient in ceramide. LDL-ceramide induced a proinflammatory response in cultured macrophages via toll-like receptor–dependent and –independent mechanisms. Finally, infusing LDL-ceramide into lean mice reduced insulin-stimulated glucose uptake, and this was due to impaired insulin action specifically in skeletal muscle. These newly identified roles of LDL-ceramide suggest that strategies aimed at reducing hepatic ceramide production or reducing ceramide packaging into lipoproteins may improve skeletal muscle insulin action.
Publisher: American Physiological Society
Date: 03-2010
DOI: 10.1152/AJPENDO.00417.2009
Abstract: Chronic inflammation is an important etiology underlying obesity-related disorders such as insulin resistance and type 2 diabetes, and recent findings indicate that the macrophage can be the initiating cell type responsible for this chronic inflammatory state. The mammalian silent information regulator 2 homolog SIRT1 modulates several physiological processes important for life span, and a potential role of SIRT1 in the regulation of insulin sensitivity has been shown. However, with respect to inflammation, the role of SIRT1 in regulating the proinflammatory pathway within macrophages is poorly understood. Here, we show that knockdown of SIRT1 in the mouse macrophage RAW264.7 cell line and in intraperitoneal macrophages broadly activates the JNK and IKK inflammatory pathways and increases LPS-stimulated TNFα secretion. Moreover, gene expression profiles reveal that SIRT1 knockdown leads to an increase in inflammatory gene expression. We also demonstrate that SIRT1 activators inhibit LPS-stimulated inflammatory pathways, as well as secretion of TNFα, in a SIRT1-dependent manner in RAW264.7 cells and in primary intraperitoneal macrophages. Treatment of Zucker fatty rats with a SIRT1 activator leads to greatly improved glucose tolerance, reduced hyperinsulinemia, and enhanced systemic insulin sensitivity during glucose cl studies. These in vivo insulin-sensitizing effects were accompanied by a reduction in tissue inflammation markers and a decrease in the adipose tissue macrophage proinflammatory state, fully consistent with the in vitro effects of SIRT1 in macrophages. In conclusion, these results define a novel role for SIRT1 as an important regulator of macrophage inflammatory responses in the context of insulin resistance and raise the possibility that targeting of SIRT1 might be a useful strategy for treating the inflammatory component of metabolic diseases.
Publisher: American Physiological Society
Date: 08-2018
DOI: 10.1152/AJPENDO.00435.2017
Abstract: Skeletal muscle is the major site of postprandial peripheral glucose uptake, but in obesity-induced insulin-resistant states insulin-stimulated glucose disposal is markedly impaired. Despite the importance of skeletal muscle in regulating glucose homeostasis, the specific transcriptional changes associated with insulin-sensitive vs. -resistant states in muscle remain to be fully elucidated. Herein, using an RNA-seq approach we identified 20 genes differentially expressed in an insulin-resistant state in skeletal muscle, including cysteine- and glycine-rich protein 3 ( Csrp3), which was highly expressed in insulin-sensitive conditions but significantly reduced in the insulin-resistant state. CSRP3 has erse functional roles including transcriptional regulation, signal transduction, and cytoskeletal organization, but its role in glucose homeostasis has yet to be explored. Thus, we investigated the role of CSRP3 in the development of obesity-induced insulin resistance in vivo. High-fat diet-fed CSRP3 knockout (KO) mice developed impaired glucose tolerance and insulin resistance as well as increased inflammation in skeletal muscle compared with wild-type (WT) mice. CSRP3-KO mice had significantly impaired insulin signaling, decreased GLUT4 translocation to the plasma membrane, and enhanced levels of phospho-PKCα in muscle, which all contributed to reduced insulin-stimulated glucose disposal in muscle in HFD-fed KO mice compared with WT mice. CSRP3 is a highly inducible protein and its expression is acutely increased after fasting. After 24h fasting, glucose tolerance was significantly improved in WT mice, but this effect was blunted in CSRP3-KO mice. In summary, we identify a novel role for Csrp3 expression in skeletal muscle in the development of obesity-induced insulin resistance.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 13-04-2016
DOI: 10.1126/SCITRANSLMED.AAD3815
Abstract: ERα action in skeletal muscle is involved in the preservation of mitochondrial health and insulin sensitivity in female mice and can serve as a defense against metabolic disease in women.
Publisher: Elsevier BV
Date: 02-2012
DOI: 10.1016/J.PMR.2011.11.015
Abstract: This article provides an overview of the structure and function of the National Skeletal Muscle Research Center (NSMRC) at the University of California, San Diego, which is one of the 7 research centers of the Medical Rehabilitation Research Infrastructure Network, created to facilitate access for physicians to experts, technology, and resources from scientific fields related to medical rehabilitation. The 4 cores of the NSMRC are described as a resource for rehabilitation medicine practitioners to use for clinically relevant muscle research.
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1194/JLR.M029355
Publisher: American Society for Clinical Investigation
Date: 02-09-2008
DOI: 10.1172/JCI34260
Publisher: American Society for Clinical Investigation
Date: 11-2011
DOI: 10.1172/JCI58554
Publisher: JMIR Publications Inc.
Date: 30-03-2021
Abstract: any older adults spend the majority of their waking hours sitting, which increases their risk of chronic diseases. Given the challenges that many older adults face when engaging in moderate-to-vigorous physical activity, understanding the health benefits of decreasing sitting time and increasing the number of sit-to-stand transitions is needed to address this growing public health concern. he aim of this 3-arm randomized controlled trial is to investigate how changes in sitting time and brief sit-to-stand transitions impact biomarkers of healthy aging and physical, emotional, and cognitive functioning compared with a healthy attention control arm. edentary and postmenopausal women (N=405) will be recruited and randomly assigned to 1 of the 3 study conditions for 3 months: healthy living attention control (Healthy Living), reduce sitting time (Reduce Sitting), and increase sit-to-stand transitions (Increase Transitions). Assessments conducted at baseline and 3 months included fasting blood draw, blood pressure, anthropometric measurements, physical functioning, cognitive testing, and 7 days of a thigh-worn accelerometer (activPAL) and a hip-worn accelerometer (ActiGraph). Blood-based biomarkers of healthy aging included those associated with glycemic control (glycated hemoglobin, fasting plasma insulin and glucose, and homeostatic model assessment of insulin resistance). ecruitment began in May 2018. The intervention is ongoing, with data collection expected to continue through the end of 2022. he Rise for Health study is designed to test whether 2 different approaches to interrupting sitting time can improve healthy aging in postmenopausal women. Results from this study may inform the development of sedentary behavior guidelines and interventions to reduce sitting time in older adults. linicalTrials.gov NCT03473145 t2/show/NCT03473145 ERR1-10.2196/28684
Publisher: American Physiological Society
Date: 12-2004
DOI: 10.1152/AJPENDO.00302.2004
Abstract: We have recently reported that, during moderate intensity exercise, low muscle glycogen concentration and utilization caused by a high-fat diet is associated with a marked increase in fat oxidation with no effect on plasma glucose uptake (R d glucose). It is our hypothesis that this increase in fat oxidation compensates for low muscle glycogen, thus preventing an increase in R d glucose. Therefore, the purpose of this study was to determine whether low muscle glycogen availability increases R d glucose under conditions of impaired fat oxidation. Six cyclists exercised at 50% peak O 2 consumption (V̇o 2 peak ) for 1 h after 2 days on either a high-fat (HF, 60% fat, 24% carbohydrate) or control (CON, 22% fat, 65% carbohydrate) diet to manipulate muscle glycogen to low and normal levels, respectively. Two hours before the start of exercise, subjects ingested 80 mg of propanolol (βB), a nonselective β-adrenergic receptor blocker, to impair fat oxidation during exercise. HF significantly decreased calculated muscle glycogen oxidation ( P 0.05), and this decrease was partly compensated for by an increase in fat oxidation ( P 0.05), accompanied by an increase in whole body lipolysis ( P 0.05), despite the presence of βB. Although HF increased fat oxidation, plasma glucose appearance rate, R d glucose, and glucose clearance rate were also significantly increased by 13, 15, and 26%, respectively (all P 0.05). In conclusion, when lipolysis and fat oxidation are impaired, in this case by βB, fat oxidation cannot completely compensate for a reduction in muscle glycogen utilization, and consequently plasma glucose turnover increases. These findings suggest that there is a hierarchy of substrate compensation for reduced muscle glycogen availability after a high-fat, low-carbohydrate diet, with fat being the primary and plasma glucose the secondary compensatory substrate. This apparent hierarchy likely serves to protect against hypoglycemia when endogenous glucose availability is low.
Publisher: Springer Science and Business Media LLC
Date: 05-10-2008
DOI: 10.1038/NATURE07349
Publisher: American Diabetes Association
Date: 13-09-2012
DOI: 10.2337/DB11-1433
Abstract: Obese white adipose tissue (AT) is characterized by large-scale infiltration of proinflammatory macrophages, in parallel with systemic insulin resistance however, the cellular stimulus that initiates this signaling cascade and chemokine release is still unknown. The objective of this study was to determine the role of the phosphoinositide 3-kinase (PI3K) regulatory subunits on AT macrophage (ATM) infiltration in obesity. Here, we find that the Pik3r1 regulatory subunits (i.e., p85α 55α 50α) are highly induced in AT from high-fat diet–fed obese mice, concurrent with insulin resistance. Global heterozygous deletion of the Pik3r1 regulatory subunits (αHZ), but not knockout of Pik3r2 (p85β), preserves whole-body, AT, and skeletal muscle insulin sensitivity, despite severe obesity. Moreover, ATM accumulation, proinflammatory gene expression, and ex vivo chemokine secretion in obese αHZ mice are markedly reduced despite endoplasmic reticulum (ER) stress, hypoxia, adipocyte hypertrophy, and Jun NH2-terminal kinase activation. Furthermore, bone marrow transplant studies reveal that these improvements in obese αHZ mice are independent of reduced Pik3r1 expression in the hematopoietic compartment. Taken together, these studies demonstrate that Pik3r1 expression plays a critical role in mediating AT insulin sensitivity and, more so, suggest that reduced PI3K activity is a key step in the initiation and propagation of the inflammatory response in obese AT.
Publisher: Elsevier BV
Date: 06-2014
Publisher: Springer Science and Business Media LLC
Date: 25-04-2022
Publisher: Wiley
Date: 26-09-2016
DOI: 10.1002/MUS.25379
Publisher: American Physiological Society
Date: 11-2014
DOI: 10.1152/AJPENDO.00001.2014
Abstract: Skeletal muscle sirtuin 1 (SIRT1) expression is reduced under insulin-resistant conditions, such as those resulting from high-fat diet (HFD) feeding and obesity. Herein, we investigated whether constitutive activation of SIRT1 in skeletal muscle prevents HFD-induced muscle insulin resistance. To address this, mice with muscle-specific overexpression of SIRT1 (mOX) and wild-type (WT) littermates were fed a control diet (10% calories from fat) or HFD (60% of calories from fat) for 12 wk. Magnetic resonance imaging and indirect calorimetry were used to measure body composition and energy expenditure, respectively. Whole body glucose metabolism was assessed by oral glucose tolerance test, and insulin-stimulated glucose uptake was measured at a physiological insulin concentration in isolated soleus and extensor digitorum longus muscles. Although SIRT1 was significantly overexpressed in muscle of mOX vs. WT mice, body weight and percent body fat were similarly increased by HFD for both genotypes, and energy expenditure was unaffected by diet or genotype. Importantly, impairments in glucose tolerance and insulin-mediated activation of glucose uptake in skeletal muscle that occurred with HFD feeding were not prevented in mOX mice. In contrast, mOX mice showed enhanced postischemic cardiac functional recovery compared with WT mice, confirming the physiological functionality of the SIRT1 transgene in this mouse model. Together, these results demonstrate that activation of SIRT1 in skeletal muscle alone does not prevent HFD-induced glucose intolerance, weight gain, or insulin resistance.
Publisher: American Physiological Society
Date: 15-04-2013
DOI: 10.1152/PHYSIOLGENOMICS.00132.2012
Abstract: In this work, the interaction between the loss of a primary component of the skeletal muscle cytoskeleton, desmin, and two common physiological stressors, acute mechanical injury and aging, were investigated at the transcriptional, protein, and whole muscle levels. The transcriptional response of desmin knockout ( des −/− ) plantarflexors to a bout of 50 eccentric contractions (ECCs) showed substantial overlap with the response in wild-type ( wt) muscle. However, changes in the expression of genes involved in muscle response to injury were blunted in adult des −/− muscle compared with wt (fold change with ECC in des −/− and wt, respectively: Mybph, 1.4 and 2.9 Xirp1, 2.2 and 5.7 Csrp3, 1.8 and 4.3), similar to the observed blunted mechanical response (torque drop: des −/− 30.3% and wt 55.5%). Interestingly, in the absence of stressors, des −/− muscle exhibited elevated expression of many these genes compared with wt. The largest transcriptional changes were observed in the interaction between aging and the absence of desmin, including many genes related to slow fiber pathway (Myh7, Myl3, Atp2a2, and Casq2) and insulin sensitivity (Tlr4, Trib3, Pdk3, and Pdk4). Consistent with these transcriptional changes, adult des −/− muscle exhibited a significant fiber type shift from fast to slow isoforms of myosin heavy chain ( wt, 5.3% IIa and 71.7% IIb des −/− , 8.4% IIa and 61.4% IIb) and a decreased insulin-stimulated glucose uptake ( wt, 0.188 μmol/g muscle/20 min des −/− , 0.085 μmol/g muscle/20 min). This work points to novel areas of influence of this cytoskeletal protein and directs future work to elucidate its function.
Publisher: American Physiological Society
Date: 02-2020
DOI: 10.1152/AJPENDO.00370.2019
Abstract: Sirtuin 1 (SIRT1) and general control of amino acid synthesis 5 (GCN5) regulate mitochondrial biogenesis via opposing modulation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) acetylation status and activity. However, the combined contribution of SIRT1 and GCN5 to skeletal muscle metabolism and endurance performance in vivo is unknown. In this study, we investigated the impact of combined skeletal muscle-specific overexpression of SIRT1 and deletion of GCN5 on glucose homeostasis, skeletal muscle mitochondrial biogenesis and function, and metabolic adaptation to endurance exercise training in mice. We generated mice with combined and tamoxifen-inducible skeletal muscle-specific overexpression of SIRT1 and knockout of GCN5 (dTG) and floxed [wild type (WT)] littermates using a Cre-LoxP approach. All mice were treated with tamoxifen at 5–6 wk of age, and 4–7 wk later glucose homeostasis, skeletal muscle contractile function, mitochondrial function, and the effects of 14 days of voluntary wheel running on expression of metabolic proteins and exercise capacity were assessed. There was no difference in oral glucose tolerance, skeletal muscle contractile function, mitochondrial abundance, or maximal respiratory capacity between dTG and WT mice. Additionally, there were no genotype differences in exercise performance and markers of mitochondrial biogenesis after 14 days of voluntary wheel running. These results demonstrate that combined overexpression of SIRT1 and loss of GCN5 in vivo does not promote metabolic remodeling in skeletal muscle of sedentary or exercise-trained mice.
Publisher: Public Library of Science (PLoS)
Date: 02-01-2018
Publisher: The Endocrine Society
Date: 09-2005
DOI: 10.1210/JC.2005-0559
Abstract: Alterations in dietary macronutrient intake can influence protein turnover. The purpose of this study was to assess the influence of a low-carbohydrate/high-protein diet (LC/HP) on skeletal muscle protein synthesis and whole-body proteolysis, without the confounding influence of a negative energy balance. Nine-day dietary intervention was applied. Subjects remained in the General Clinical Research Center throughout the 9-d study. Eight young, healthy volunteers participated. Subjects ate a typical Western diet (60% carbohydrate, 30% fat, 10% protein) for 2 d, followed immediately by 7 d of an isocaloric LC/HP (5% carbohydrate, 60% fat, 35% protein). Skeletal muscle fractional synthetic rate and whole-body proteolysis [leucine rate of appearance in plasma (Ra)] were measured after an overnight fast before and after 2 and 7 d of LC/HP. We also measured plasma concentrations of insulin, GH, and IGF-I. Leucine Ra was increased (P = 0.03) after 2 and 7 d of LC/HP, and muscle fractional synthetic rate was approximately 2-fold higher (P < 0.01) after 7 d of LC/HP. Fat free mass was not altered by LC/HP. Average 24-h plasma insulin concentration was 50% lower (P < 0.001) after 2 and 7 d of LC/HP, whereas GH secretion and total plasma IGF-I concentrations were unchanged with LC/HP. However, plasma free IGF-I decreased by approximately 30% after 7 d of LC/HP (P = 0.002), whereas muscle IGF-I mRNA increased about 2-fold (P = 0.05). Increasing dietary protein content during a 7-d carbohydrate restricted diet stimulated muscle protein synthesis and whole-body proteolysis without a measurable change in fat free mass.
Publisher: American Physiological Society
Date: 08-2005
DOI: 10.1152/AJPENDO.00069.2005
Abstract: Dietary carbohydrate restriction (CR) presents a challenge to glucose homeostasis. Despite the popularity of CR diets, little is known regarding the metabolic effects of CR. The purpose of this study was to examine changes in whole body carbohydrate oxidation, glucose availability, endogenous glucose production, and peripheral glucose uptake after dietary CR, without the confounding influence of a negative energy balance. Postabsorptive rates of glucose appearance in plasma (R a i.e., endogenous glucose production) and disappearance from plasma (R d i.e., glucose uptake) were measured using isotope dilution methods after a conventional diet [60% carbohydrate (CHO), 30% fat, and 10% protein kcals = 1.3 × resting energy expenditure (REE)] and after 2 days and 7 days of CR (5% CHO, 60% fat, and 35% protein kcals = 1.3 × REE) in eight subjects (means ± SE 29 ± 4 yr BMI 24 ± 1 kg/m 2 ) during a 9-day hospital visit. Postabsorptive plasma glucose concentration was reduced ( P = 0.01) after 2 days but returned to prediet levels the next day and remained at euglycemic levels throughout the diet (5.1 ± 0.2, 4.3 ± 0.3, and 4.8 ± 0.4 mmol/l for prediet, 2 days and 7 days, respectively). Glucose R a and glucose R d were reduced to below prediet levels (9.8 ± 0.6 μmol·kg −1 ·min −1 ) after 2 days of CR (7.9 ± 0.3 μmol·kg −1 ·min −1 ) and remained suppressed after 7 days (8.3 ± 0.4 μmol·kg −1 ·min −1 both P 0.001). A greater suppression in carbohydrate oxidation, compared with the reduction in glucose R d , led to an increased (all P ≤ 0.05) rate of nonoxidative glucose disposal at 7 days (5.2 ± 0.5 μmol·kg −1 ·min −1 ), compared with 2 days (2.7 ± 0.5 μmol·kg −1 ·min −1 ) and prediet (1.6 ± 0.8 μmol·kg −1 ·min −1 ). In response to eucaloric CR, a marked increase in nonoxidative glucose disposal may help maintain systemic glucose availability.
Publisher: Springer Science and Business Media LLC
Date: 19-04-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2013
Publisher: S. Karger AG
Date: 2014
DOI: 10.1159/000357336
Abstract: This chapter summarizes current knowledge regarding the interaction between lipid availability, endurance exercise, and insulin sensitivity. We discuss the role of lipid availability as a key mediator of insulin resistance in obesity, the proposed cellular mechanisms underlying this relationship, recent studies demonstrating that acute exercise protects against lipid-induced insulin resistance, how fatty acid partitioning may contribute to this protective effect of endurance exercise and finally remaining questions and future directions in the field.
Publisher: Cold Spring Harbor Laboratory
Date: 04-02-2023
DOI: 10.1101/2023.02.03.527012
Abstract: Subcutaneous white adipose tissue (scWAT) is a dynamic storage and secretory organ that regulates systemic homeostasis, yet the impact of endurance exercise training and sex on its molecular landscape has not been fully established. Utilizing an integrative multi-omics approach with data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we identified profound sexual dimorphism in the dynamic response of rat scWAT to endurance exercise training. Despite similar cardiorespiratory improvements, only male rats reduced whole-body adiposity, scWAT adipocyte size, and total scWAT triglyceride abundance with training. Multi-omic analyses of adipose tissue integrated with phenotypic measures identified sex-specific training responses including enrichment of mTOR signaling in females, while males displayed enhanced mitochondrial ribosome biogenesis and oxidative metabolism. Overall, this study reinforces our understanding that sex impacts scWAT biology and provides a rich resource to interrogate responses of scWAT to endurance training.
Publisher: American Physiological Society
Date: 11-2019
DOI: 10.1152/AJPCELL.00159.2019
Abstract: Whether the histone deacetylase (HDAC) and sirtuin families of protein deacetylases regulate insulin-stimulated glucose uptake, independent of their transcriptional effects, has not been studied. Our objective was to determine the nontranscriptional role of HDACs and sirtuins in regulation of skeletal muscle insulin action. Basal and insulin-stimulated glucose uptake and signaling and acetylation were assessed in L6 myotubes and skeletal muscle from C57BL/6J mice that were treated acutely (1 h) with HDAC (trichostatin A, panobinostat, TMP195) and sirtuin inhibitors (nicotinamide). Treatment of L6 myotubes with HDAC inhibitors or skeletal muscle with a combination of HDAC and sirtuin inhibitors increased tubulin and pan-protein acetylation, demonstrating effective impairment of HDAC and sirtuin deacetylase activities. Despite this, neither basal nor insulin-stimulated glucose uptake or insulin signaling was impacted. Acute reduction of the deacetylase activity of HDACs and/or sirtuins does not impact insulin action in skeletal muscle.
Publisher: Springer Science and Business Media LLC
Date: 02-05-2015
DOI: 10.1038/IJO.2014.70
Publisher: American Physiological Society
Date: 06-2021
DOI: 10.1152/JAPPLPHYSIOL.00065.2021
Abstract: Here, we demonstrate that glucose uptake in response to ex vivo contractions is not affected by the loss of sirtuin 1 (SIRT1) deacetylase function in muscle, regardless of sex or muscle type. Interestingly, however, similar to studies on insulin-stimulated glucose uptake, we demonstrate that contraction-stimulated glucose uptake is robustly higher in female compared with the male skeletal muscle. To our knowledge, this is the first demonstration of sex-based differences in contraction-stimulated glucose uptake in skeletal muscle.
Publisher: Springer Science and Business Media LLC
Date: 27-07-2012
Publisher: American Physiological Society
Date: 03-2012
Publisher: Cold Spring Harbor Laboratory
Date: 29-06-2022
DOI: 10.1101/2022.06.27.497838
Abstract: Muscle mass and strength are predictors of longevity. We have previously identified a series of molecular brakes that slow muscle growth in response to stress. One potential stress that we hypothesized would limit muscle growth is caloric stress through the activation of SIRT1. We therefore identified natural product inhibitors of SIRT1 and tested their effects on load-induced increases in muscle fiber cross-sectional area (fCSA) using an incomplete factorial design. Supplying varying amounts of three natural products for the full two-week period of overload resulted in increases in fCSA that varied from −2 to 113%. Using these data, we produced a model that predicted the optimal combination and concentration of each natural product and validated this model in a separate cohort of animals. Following two weeks of overload, fCSA in the optimal group increased 62%, whereas in the placebo fCSA increased only 3%. The greater increase in fCSA was not the result of an increase in ribosomal mass. In fact, the optimal group showed significantly less of the 5⍰ external transcribed spacer, a marker of 47S ribosomal RNA synthesis, and a trend for decreased total RNA. In spite of the lower ribosome mass, the increase in protein synthesis was similar, suggesting that the natural product cocktail may be increasing ribosomal efficiency rather than capacity. These data suggest that inhibition of SIRT1, together with exercise, may be useful in increasing muscle fCSA.
Publisher: Wiley
Date: 15-09-2015
DOI: 10.1113/JP271219
Publisher: Public Library of Science (PLoS)
Date: 22-09-2014
Publisher: American Physiological Society
Date: 05-2010
DOI: 10.1152/AJPENDO.00668.2009
Abstract: Tissue macrophage inflammatory pathways contribute to obesity-associated insulin resistance. Here, we have examined the efficacy and mechanisms of action of a novel anti-inflammatory compound (HE3286) in vitro and in vivo. In primary murine macrophages, HE3286 attenuates LPS- and TNFα-stimulated inflammation. In Zucker diabetic fatty rats, inflammatory cytokine/chemokine expression was downregulated in liver and adipose tissue by HE3286 treatment, as was macrophage infiltration into adipose tissue. In line with reduced inflammation, HE3286 treatment normalized fasting and fed glucose levels, improved glucose tolerance, and enhanced skeletal muscle and liver insulin sensitivity, as assessed by hyperinsulinemic euglycemic cl studies. In phase 2 clinical trials, HE3286 treatment led to an enhancement in insulin sensitivity in humans. Gluconeogenic capacity was also reduced by HE3286 treatment, as evidenced by a reduced glycemic response during pyruvate tolerance tests and decreased basal hepatic glucose production (HGP) rates. Since serum levels of gluconeogenic substrates were decreased by HE3286, it indicates that the reduction of both intrinsic gluconeogenic capacity and substrate availability contributes to the decrease in HGP. Lipidomic analysis revealed that HE3286 treatment reduced liver cholesterol and triglyceride content, leading to a feedback elevation of LDL receptor and HMG-CoA reductase expression. Accordingly, HE3286 treatment markedly decreased total serum cholesterol. In conclusion, HE3286 is a novel anti-inflammatory compound, which displays both glucose-lowering and cholesterol-lowering effects.
Publisher: American Physiological Society
Date: 05-2017
Abstract: While excessive tensile strain can be detrimental to nerve function, strain can be a positive regulator of neuronal outgrowth. We used an in vivo rat model of sciatic nerve strain to investigate signaling mechanisms underlying peripheral nerve response to deformation. Nerves were deformed by 11% and did not demonstrate deficits in compound action potential latency or litude during or after 6 h of strain. As revealed by Western blotting, application of strain resulted in significant upregulation of mammalian target of rapamycin (mTOR) and S6 signaling in nerves, increased myelin basic protein (MBP) and β-actin levels, and increased phosphorylation of neurofilament subunit H (NF-H) compared with unstrained (sham) contralateral nerves ( P 0.05 for all comparisons, paired two-tailed t-test). Strain did not alter neuron-specific β3-tubulin or overall nerve tubulin levels compared with unstrained controls. Systemic rapamycin treatment, thought to selectively target mTOR complex 1 (mTORC1), suppressed mTOR/S6 signaling, reduced levels of MBP and overall tubulin, and decreased NF-H phosphorylation in nerves strained for 6 h, revealing a role for mTOR in increasing MBP expression and NF-H phosphorylation, and maintaining tubulin levels. Consistent with stretch-induced increases in MBP, immunolabeling revealed increased S6 signaling in Schwann cells of stretched nerves compared with unstretched nerves. In addition, application of strain to cultured adult dorsal root ganglion neurons showed an increase in axonal protein synthesis based on a puromycin incorporation assay, suggesting that neuronal translational pathways also respond to strain. This work has important implications for understanding mechanisms underlying nerve response to strain during development and regeneration. NEW & NOTEWORTHY Peripheral nerves experience tensile strain (stretch) during development and movement. Excessive strain impairs neuronal function, but moderate strains are accommodated by nerves and can promote neuronal growth mechanisms underlying these phenomena are not well understood. We demonstrated that levels of several structural proteins increase following physiological levels of nerve strain and that expression of a subset of these proteins is regulated by mTOR. Our work has important implications for understanding nerve development and strain-based regenerative strategies.
Publisher: American Physiological Society
Date: 10-2011
DOI: 10.1152/AJPREGU.00232.2011
Abstract: The transcriptional coactivator PGC-1α is a potent regulator of skeletal muscle metabolism. Less is known about the structurally similar PGC-1α-related coactivator (PRC) that is enriched in myoblasts and adult skeletal muscle. The present study was designed to determine the effect of PRC on the metabolic profile of C2C12 myotubes. Overexpression of full-length PRC increased PRC gene expression by 2.7 ± 0.3-fold and protein content by 108 ± 5.3%. This modest elevation in PRC resulted in an increased rate of myoblast proliferation (61.5 ± 2.7%) and resulted in myotubes characterized by increased MyoD (18.2 ± 0.52%) and myosin heavy chain (15.4 ± 3.13%) protein. PRC overexpressing myotubes showed increases in mRNA for some—COX4 (2.6 ± 0.18-fold), ATP5B (2.7 ± 0.34-fold) cytochrome c (5.1 ± 0.68-fold)—but not all, MTCO1 (0.61 ± 0.18-fold) and HAD (0.98 ± 0.36-fold) mitochondrial genes, as well as a significant increase in cytochrome– c (28.7 ± 7.02%) protein content. The enzyme activity of the electron transport chain (ETC) complex IV (3.7 ± 0.01-fold) and citrate synthase (2.1 ± 0.14-fold) was increased by PRC, as was the mtDNA:nucDNA ratio (11 ± 0.3%). PRC increased cellular respiration (142%), basal (197%) and insulin-stimulated (253%) glucose uptake, as well as palmitate uptake (28.6 ± 3.31%) and oxidation (31.1 ± 2.17%). Associated with these changes in function, PRC overexpression increased GLUT4 mRNA (4.5 ± 0.22-fold) and protein (13.8 ± 2.08%) and CPT1 protein (28.9 ± 4.23%). Electrical stimulation of C2C12 myotubes resulted in a transient increase in PRC mRNA that was smaller (2.1 ± 0.3-fold vs. 4.4 ± 0.23-fold) and occurred earlier (3 h vs. 6 h) than PGC-1α. Collectively, our data show that PRC promotes skeletal muscle myogenesis and metabolism in vitro, thus identifying PRC as a functional skeletal muscle coactivator capable of regulating mitochondrial substrate utilization and respiration.
Publisher: Informa UK Limited
Date: 03-2009
DOI: 10.1128/MCB.00705-08
Publisher: The Royal Society
Date: 12-09-2018
Abstract: Compared to other primates, humans are exceptional long-distance runners, a feature that emerged in genus Homo approximately 2 Ma and is classically attributed to anatomical and physiological adaptations such as an enlarged gluteus maximus and improved heat dissipation. However, no underlying genetic changes have currently been defined. Two to three million years ago, an exon deletion in the CMP-Neu5Ac hydroxylase ( CMAH ) gene also became fixed in our ancestral lineage. Cmah loss in mice exacerbates disease severity in multiple mouse models for muscular dystrophy, a finding only partially attributed to differences in immune reactivity. We evaluated the exercise capacity of Cmah −/− mice and observed an increased performance during forced treadmill testing and after 15 days of voluntary wheel running. Cmah −/− hindlimb muscle exhibited more capillaries and a greater fatigue resistance in situ . Maximal coupled respiration was also higher in Cmah null mice ex vivo and relevant differences in metabolic pathways were also noted. Taken together, these data suggest that CMAH loss contributes to an improved skeletal muscle capacity for oxygen use. If translatable to humans, CMAH loss could have provided a selective advantage for ancestral Homo during the transition from forest dwelling to increased resource exploration and hunter/gatherer behaviour in the open savannah.
Publisher: Springer Science and Business Media LLC
Date: 29-11-2007
DOI: 10.1038/NATURE06261
Publisher: American Physiological Society
Date: 03-2005
DOI: 10.1152/AJPENDO.00401.2004
Abstract: High plasma fatty acid availability and a positive energy balance in sedentary in iduals reduce insulin sensitivity. This study's purpose was to determine whether high plasma fatty acid availability and systemic caloric excess after exercise also impair insulin sensitivity. On two separate occasions, seven nonobese women performed 90 min of exercise at ∼65% peak oxygen uptake. In one trial, a lipid + heparin emulsion (Lipid) was infused overnight to increase plasma fatty acid availability. In the other trial, saline was infused as control. The next morning, a muscle biopsy was taken to measure muscle glycogen and intramuscular triglyceride (IMTG) concentrations. Three hours after the overnight infusion was stopped, insulin sensitivity was assessed with an intravenous glucose tolerance test, using minimal model analysis (S i ). During the overnight infusions, plasma fatty acid concentration was approximately fourfold higher [means (SD): 0.84 (0.36) vs. 0.22 (0.09) mmol/l P = 0.003], and the next morning IMTG concentration was ∼30% greater [49.2 (6.6) vs. 38.3 (7.7) mmol/kg dry wt P = 0.036] in Lipid compared with saline. However, muscle glycogen concentration was not different between trials ( P = 0.82). Lipid caused a 24-h surplus of ∼1100 kcal above energy balance ( P = 0.00001), whereas energy balance was maintained in saline. Despite these differences in fatty acid and energy availability, S i the morning after exercise was not different between trials ( P = 0.72). Thus insulin sensitivity the morning after a single exercise session was not reduced despite overnight exposure to a fourfold increase in plasma fatty acid concentration, elevated IMTG concentration, and systemic delivery of ∼1,100-kcal excess.
Publisher: American Physiological Society
Date: 09-2017
DOI: 10.1152/AJPCELL.00100.2017
Abstract: Although the signal pathways mediating muscle protein synthesis and degradation are well characterized, the transcriptional processes modulating skeletal muscle mass and adaptive growth are poorly understood. Recently, studies in mouse models of muscle wasting or acutely exercised human muscle have suggested a potential role for the transcription factor signal transducer and activator of transcription 3 (STAT3), in adaptive growth. Hence, in the present study we sought to define the contribution of STAT3 to skeletal muscle adaptive growth. In contrast to previous work, two different resistance exercise protocols did not change STAT3 phosphorylation in human skeletal muscle. To directly address the role of STAT3 in load-induced (i.e., adaptive) growth, we studied the anabolic effects of 14 days of synergist ablation (SA) in skeletal muscle-specific STAT3 knockout (mKO) mice and their floxed, wild-type (WT) littermates. Plantaris muscle weight and fiber area in the nonoperated leg (control CON) was comparable between genotypes. As expected, SA significantly increased plantaris weight, muscle fiber cross-sectional area, and anabolic signaling in WT mice, although interestingly, this induction was not impaired in STAT3 mKO mice. Collectively, these data demonstrate that STAT3 is not required for overload-mediated hypertrophy in mouse skeletal muscle.
Publisher: American Physiological Society
Date: 10-2019
DOI: 10.1152/JAPPLPHYSIOL.00003.2019
Abstract: Signal transducer and activator of transcription 3 (STAT3) was recently found to be localized to mitochondria in a number of tissues and cell types, where it modulates oxidative phosphorylation via interactions with the electron transport proteins, complex I and complex II. Skeletal muscle is densely populated with mitochondria although whether STAT3 contributes to skeletal muscle oxidative capacity is unknown. In the present study, we sought to elucidate the contribution of STAT3 to mitochondrial and skeletal muscle function by studying mice with muscle-specific knockout of STAT3 (mKO). First, we developed a novel flow cytometry-based approach to confirm that STAT3 is present in skeletal muscle mitochondria. However, contrary to findings in other tissue types, complex I and complex II activity and maximal mitochondrial respiratory capacity in skeletal muscle were comparable between mKO mice and floxed/wild-type littermates. Moreover, there were no genotype differences in endurance exercise performance, skeletal muscle force-generating capacity, or the adaptive response of skeletal muscle to voluntary wheel running. Collectively, although we confirm the presence of STAT3 in skeletal muscle mitochondria, our data establish that STAT3 is dispensable for mitochondrial and physiological function in skeletal muscle. NEW & NOTEWORTHY Whether signal transducer and activator of transcription 3 (STAT3) can regulate the activity of complex I and II of the electron transport chain and mitochondrial oxidative capacity in skeletal muscle, as it can in other tissues, is unknown. By using a mouse model lacking STAT3 in muscle, we demonstrate that skeletal muscle mitochondrial and physiological function, both in vivo and ex vivo, is not impacted by the loss of STAT3.
Publisher: Wiley
Date: 21-04-2016
DOI: 10.1002/JOR.23256
Publisher: Springer Science and Business Media LLC
Date: 18-10-2017
DOI: 10.1038/S41598-017-14081-W
Abstract: Enhanced coverage and sensitivity of next-generation ‘omic’ platforms has allowed the characterization of gene, metabolite and protein responses in highly metabolic tissues, such as, skeletal muscle. A limitation, however, is the capability to determine interaction between dynamic biological networks. To address this limitation, we applied Weighted Analyte Correlation Network Analysis (WACNA) to RNA-seq and metabolomic datasets to identify correlated subnetworks of transcripts and metabolites in response to a high-fat diet (HFD)-induced obesity and/or exercise. HFD altered skeletal muscle lipid profiles and up-regulated genes involved in lipid catabolism, while decreasing 241 exercise-responsive genes related to skeletal muscle plasticity. WACNA identified the interplay between transcript and metabolite subnetworks linked to lipid metabolism, inflammation and glycerophospholipid metabolism that were associated with IL6, AMPK and PPAR signal pathways. Collectively, this novel experimental approach provides an integrative resource to study transcriptional and metabolic networks in skeletal muscle in the context of health and disease.
Publisher: American Society for Clinical Investigation
Date: 06-2007
DOI: 10.1172/JCI30566
Publisher: Elsevier BV
Date: 04-2017
Publisher: American Physiological Society
Date: 11-2014
DOI: 10.1152/AJPCELL.00399.2013
Abstract: It is well established that exercise elicits a finely tuned adaptive response in skeletal muscle, with contraction frequency, duration, and recovery shaping skeletal muscle plasticity. Given the power of physical activity to regulate metabolic health, numerous research groups have focused on the molecular mechanisms that sense, interpret, and translate this contractile signal into postexercise adaptation. While our current understanding is that contraction-sensitive allosteric factors (e.g., Ca 2+ , AMP, NAD + , and acetyl-CoA) initiate signaling changes, how the muscle translates changes in these factors into the appropriate adaptive response remains poorly understood. During the past decade, systems biology approaches, utilizing “omics” screening techniques, have allowed researchers to define global processes of regulation with incredible sensitivity and specificity. As a result, physiologists are now able to study substrate flux with stable isotope tracers in combination with metabolomic approaches and to coordinate these functional changes with proteomic and transcriptomic analysis. In this review, we highlight lysine acetylation as an important posttranslational modification in skeletal muscle. We discuss the evolution of acetylation research and detail how large proteomic screens in erse metabolic systems have led to the current hypothesis that acetylation may be a fundamental mechanism to fine-tune metabolic adaptation in skeletal muscle.
Publisher: Oxford University Press (OUP)
Date: 18-01-2021
DOI: 10.1093/PTJ/PZAB011
Publisher: Elsevier BV
Date: 09-2020
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.EXGER.2022.111831
Abstract: This study aimed to evaluate the impact of a 12-week calorie-restricted diet and recreational sports training on gene expressions IL-15, ATROGIN-1 and MURF-1 in skeletal muscle of T2D patients. Older adults with T2D (n = 39, 60 ± 6.0 years, BMI 33.5 ± 0.6 kg/m Total body weight was reduced in ~4 kg representing body fat mass in all groups after 12-weeks (P < 0.05). HbA1c values decreased in all groups post-intervention. Lipids profile improved in the training groups (P < 0.05) after 12-weeks. ATROGIN-1 and MURF-1 mRNA reduced in the DS (1.084 ± 0.14 vs. 0.754 ± 1.14 and 1.175 ± 0.34 vs. 0.693 ± 0.12, respectively P < 0.05), while IL-15 mRNA increased in the DR (1.056 ± 0.12 vs. 1.308 ± 0.13 P < 0.05) after 12-weeks intervention. Recreational training with a moderate calorie-restricted diet can downregulates the expression of atrophy-associated myokines and increases the expression of anti-inflammatory gene IL-15.
Publisher: Elsevier BV
Date: 09-2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2017
Abstract: Cellular remodeling in rotator cuff muscles following a massive rotator cuff tear is poorly understood. The aim of the current study was to provide histological evidence to elucidate the mode of muscle loss in advanced human rotator cuff disease and to assess tissue-level changes in relation to findings on noninvasive imaging. Rotator cuff muscle biopsy s les were taken from the scapular fossae from 23 consecutive patients undergoing reverse total shoulder arthroplasty in order to evaluate muscle composition in severe rotator cuff disease. Markers of vascularity inflammation fat distribution and muscle atrophy, degeneration, and regeneration were quantified. The s les primarily consisted of dense, organized connective tissue (48.2% ± 19.1%) and disorganized, loose connective tissue (36.9% ± 15.9%), with substantially smaller fractions of muscle (10.4% ± 22.0%) and fat (6.5% ± 11.6%). Only 25.8% of the biopsy pool contained any muscle fibers at all. Increased inflammatory cell counts (111.3 ± 81.5 macrophages/mm 2 ) and increased vascularization (66.6 ± 38.0 vessels/mm 2 ) were observed across biopsies. Muscle fiber degeneration was observed in 90.0% ± 15.6% of observable muscle fascicles, and the percentage of centrally nucleated muscle fibers was pathologically elevated (11.3% ± 6.3%). Fat accumulation was noted in both perifascicular (60.7% ± 41.4%) and intrafascicular (42.2% ± 33.6%) spaces, with evidence that lipid may replace contractile elements without altering muscle organization. Dramatic degeneration and inflammation of the rotator cuff muscles are characteristics of the most chronic and severe rotator cuff disease states, suggesting that muscle loss is more complicated than, and distinct from, the simple atrophy found in less severe cases. In order to address degenerative muscle loss, alternative therapeutic approaches directed at muscle regeneration must be considered if muscle function is to be restored in late-stage rotator cuff disease.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 17-09-2014
DOI: 10.2106/JBJS.M.01585
Publisher: Cold Spring Harbor Laboratory
Date: 13-01-2023
DOI: 10.1101/2023.01.13.523698
Abstract: Mitochondria are adaptable organelles with erse cellular functions critical to whole-body metabolic homeostasis. While chronic endurance exercise training is known to alter mitochondrial activity, these adaptations have not yet been systematically characterized. Here, the Molecular Transducers of Physical Activity Consortium (MoTrPAC) mapped the longitudinal, multi-omic changes in mitochondrial analytes across 19 tissues in male and female rats endurance trained for 1, 2, 4 or 8 weeks. Training elicited substantial changes in the adrenal gland, brown adipose, colon, heart and skeletal muscle, while we detected mild responses in the brain, lung, small intestine and testes. The colon response was characterized by non-linear dynamics that resulted in upregulation of mitochondrial function that was more prominent in females. Brown adipose and adrenal tissues were characterized by substantial downregulation of mitochondrial pathways. Training induced a previously unrecognized robust upregulation of mitochondrial protein abundance and acetylation in the liver, and a concomitant shift in lipid metabolism. The striated muscles demonstrated a highly coordinated response to increase oxidative capacity, with the majority of changes occurring in protein abundance and post-translational modifications. We identified exercise upregulated networks that are downregulated in human type 2 diabetes and liver cirrhosis. In both cases HSD17B10, a central dehydrogenase in multiple metabolic pathways and mitochondrial tRNA maturation, was the main hub. In summary, we provide a multi-omic, cross-tissue atlas of the mitochondrial response to training and identify candidates for prevention of disease-associated mitochondrial dysfunction.
Publisher: American Physiological Society
Date: 08-2012
DOI: 10.1152/AJPENDO.00054.2012
Abstract: The pyridine nucleotides, NAD + and NADH, are coenzymes that provide oxidoreductive power for the generation of ATP by mitochondria. In skeletal muscle, exercise perturbs the levels of NAD + , NADH, and consequently, the NAD + /NADH ratio, and initial research in this area focused on the contribution of redox control to ATP production. More recently, numerous signaling pathways that are sensitive to perturbations in NAD + (H) have come to the fore, as has an appreciation for the potential importance of compartmentation of NAD + (H) metabolism and its subsequent effects on various signaling pathways. These pathways, which include the sirtuin (SIRT) proteins SIRT1 and SIRT3, the poly(ADP-ribose) polymerase (PARP) proteins PARP1 and PARP2, and COOH-terminal binding protein (CtBP), are of particular interest because they potentially link changes in cellular redox state to both immediate, metabolic-related changes and transcriptional adaptations to exercise. In this review, we discuss what is known, and not known, about the contribution of NAD + (H) metabolism and these aforementioned proteins to mitochondrial adaptations to acute and chronic endurance exercise.
Publisher: American Physiological Society
Date: 03-2010
DOI: 10.1152/JAPPLPHYSIOL.01106.2009
Abstract: The content of meals consumed after exercise can impact metabolic responses for hours and even days after the exercise session. The purpose of this study was to compare the effect of low dietary carbohydrate (CHO) vs. low energy intake in meals after exercise on insulin sensitivity and lipid metabolism the next day. Nine healthy men participated in four randomized trials. During the control trial (CON) subjects remained sedentary. During the other three trials, subjects exercised [65% peak oxygen consumption (V̇o 2peak ) cycle ergometer and treadmill exercise] until they expended ∼800 kcal. Dietary intake during CON and one exercise trial (BAL) was designed to provide sufficient energy and carbohydrate to maintain nutrient balance. In contrast, the diets after the other two exercise trials were low in either CHO (LOW-CHO) or energy (LOW-EN). The morning after exercise we obtained a muscle biopsy, assessed insulin sensitivity (S i intravenous glucose tolerance test) and measured lipid kinetics (isotope tracers). Although subjects were in energy balance during both LOW-CHO and CON, the lower muscle glycogen concentration during LOW-CHO vs. CON (402 ± 29 vs. 540 ± 33 mmol/kg dry wt, P 0.01) coincided with a significant increase in S i [5.2 ± 0.7 vs. 3.8 ± 0.7 (mU/l) −1 ·min −1 P 0.05]. Conversely, despite ingesting several hundred fewer kilocalories after exercise during LOW-EN compared with BAL, this energy deficit did not affect S i the next day [4.9 ± 0.9, and 5.0 ± 0.8 (mU/l) −1 ·min −1 ]. Maintaining an energy deficit after exercise had the most potent effect on lipid metabolism, as measured by a higher plasma triacylglycerol concentration, and increased plasma fatty acid mobilization and oxidation compared with when in nutrient balance. Carbohydrate deficit after exercise, but not energy deficit, contributed to the insulin-sensitizing effects of acute aerobic exercise, whereas maintaining an energy deficit after exercise augmented lipid mobilization.
Publisher: Elsevier BV
Date: 06-2011
Publisher: Public Library of Science (PLoS)
Date: 22-01-2021
DOI: 10.1371/JOURNAL.PONE.0245594
Abstract: While obesity and insulin resistance are known risk factors for wound complications after total joint arthroplasty (TJA), the biologic causes remain to be elucidated. Recently, neutrophil extracellular trap formation (NETosis) was identified as a mediator of delayed wound healing in insulin resistant states. Herein, we explored the relationship between obesity, insulin resistance and biomarkers of NET formation in TJA subjects. We enrolled 14 obese (body mass index [BMI]≥30 kg/m 2 ), and 15 lean (BMI kg/m 2 ) subjects undergoing primary knee or hip TJA. On the day of surgery, skeletal muscle proximal to the operated joint and plasma were collected. Protein abundance of NETosis biomarkers, peptidylarginine deaminase 4 (PAD4) and neutrophil elastase (NE) were assessed in skeletal muscle by immunoblotting and metabolic parameters (glucose, insulin, triglycerides, free fatty acids) and cell-free double-stranded DNA (cf-dsDNA) were assessed in plasma and were correlated with obesity and insulin resistance (as measured by the homeostatic model assessment for insulin resistance). When comparing lean and obese subjects, there were no significant differences in plasma cf-dsDNA or skeletal muscle NE or PAD4 abundance. In contrast, skeletal muscle PAD4 abundance, but not NE or plasma cf-dsDNA, was positively correlated with insulin resistance. Compared to insulin sensitive subjects, insulin resistant TJA subjects have higher expression of PAD4 at the surgical site and therefore may have higher rates of NET formation, which may lead to delayed surgical site wound healing.
Publisher: American Society for Clinical Investigation
Date: 11-01-2022
Publisher: Elsevier BV
Date: 11-2009
Publisher: Wiley
Date: 28-12-2016
DOI: 10.1096/FJ.15-281741
Publisher: American Physiological Society
Date: 03-2014
DOI: 10.1152/JAPPLPHYSIOL.01072.2013
Abstract: AMPK (AMP-dependant protein kinase)-mTORC1 (mechanistic target of rapamycin in complex 1)-p70S6K1 (ribosomal protein S6 kinase 1 of 70 kDa) signaling plays a crucial role in muscle protein synthesis (MPS). Understanding this pathway has been advanced by the application of the Western blot (WB) technique. However, because many components of the mTORC1 pathway undergo numerous, multisite posttranslational modifications, solely studying the phosphorylation changes of mTORC1 and its substrates may not adequately represent the true metabolic signaling processes. The aim of this study was to develop and apply a quantitative in vitro [γ- 32 P] ATP kinase assay (KA) for p70S6K1 to assess kinase activity in human skeletal muscle to resistance exercise (RE) and protein feeding. In an initial series of experiments the assay was validated in tissue culture and in p70S6K1-knockout tissues. Following these experiments, the methodology was applied to assess p70S6K1 signaling responses to a physiologically relevant stimulus. Six men performed unilateral RE followed by the consumption of 20 g of protein. Muscle biopsies were obtained at pre-RE, and 1 and 3 h post-RE. In response to RE and protein consumption, p70S6K1 activity as assessed by the KA was significantly increased from pre-RE at 1 and 3 h post-RE. However, phosphorylated p70S6K1 thr389 was not significantly elevated. AMPK activity was suppressed from pre-RE at 3 h post-RE, whereas phosphorylated ACC ser79 was unchanged. Total protein kinase B activity also was unchanged after RE from pre-RE levels. Of the other markers we assessed by WB, 4EBP1 thr37/46 phosphorylation was the only significant responder, being elevated at 3 h post-RE from pre-RE. These data highlight the utility of the KA to study skeletal muscle plasticity.
Publisher: American Chemical Society (ACS)
Date: 06-02-2009
DOI: 10.1021/JM8012954
Abstract: A series of imidazo[1,2-b]thiazole derivatives is shown to activate the NAD(+)-dependent deacetylase SIRT1, a potential new therapeutic target to treat various metabolic disorders. This series of compounds was derived from a high throughput screening hit bearing an oxazolopyridine core. Water-solubilizing groups could be installed conveniently at either the C-2 or C-3 position of the imidazo[1,2-b]thiazole ring. The SIRT1 enzyme activity could be adjusted by modifying the amide portion of these imidazo[1,2-b]thiazole derivatives. The most potent analogue within this series, namely, compound 29, has demonstrated oral antidiabetic activity in the ob/ob mouse model, the diet-induced obesity (DIO) mouse model, and the Zucker fa/fa rat model.
Publisher: The Endocrine Society
Date: 07-2010
DOI: 10.1210/ME.2009-0462
Abstract: Recent findings denote an important contribution of macrophage inflammatory pathways in causing obesity-related insulin resistance. Inducible nitric oxide synthase (iNOS) is activated in proinflammatory macrophages and modestly elevated in insulin-responsive tissues. Although the benefits of systemic iNOS inhibition in insulin-resistant models have been demonstrated, the role of macrophage iNOS in metabolic disorders is not clear. In the current work, we used bone marrow transplantation (BMT) to generate mice with myeloid iNOS deficiency [iNOS BMT knockout (KO)]. Interestingly, disruption of iNOS in myeloid cells did not protect mice from high-fat diet-induced obesity and insulin resistance. When mice were treated with the iNOS inhibitor, N6-(1-Iminoethyl)-L-lysine hydrochloride (L-NIL), we observed a significant and comparable improvement of glucose homeostasis and insulin sensitivity in both wild-type and iNOS BMT KO mice. We further demonstrated that absence of iNOS in primary macrophages did not affect acute TLR4 signaling pathways and had only a modest and mixed effect on inflammatory gene expression. With respect to TNFα treatment, iNOS KO macrophages showed, if anything, a greater inflammatory response. In summary, we conclude that iNOS inhibition in tissues other than myeloid cells is responsible for the beneficial effects in obesity/insulin resistance.
Publisher: Wiley
Date: 13-06-2017
DOI: 10.1111/APHA.12897
Publisher: Elsevier BV
Date: 12-2017
Publisher: Mary Ann Liebert Inc
Date: 07-2017
Abstract: In cell culture studies, dried plum (Prunus domestica L.) polyphenols increased osteoblast alkaline phosphatase (ALP) activity, mineralized nodule formation, and the expression of the bone marker genes runt-related transcription factor 2 (RUNX2) and osterix. The purpose of this study was to determine whether human serum collected 1 and 2 h after dried plum ingestion influenced osteoblast cell activity and gene expression. Five healthy women ingested 100 g of dried plum, and serum s les were collected at baseline (before dried plum ingestion) and 1 and 2 h postingestion of dried plum. MC3T3-E1 osteoblast cells were treated (2% of medium) with these serum s les for 3 or 9 days. Intracellular and extracellular ALP activities were significantly increased after 3 or 9 days of treatment with serum both postingestion time points, with no effect seen in baseline s les. Also, serum obtained 1 and 2 h postingestion significantly increased the mRNA expression of bone markers RUNX2 and connexin43 (CX43) after both 3 and 9 days of incubation periods. Finally, serum obtained 1 and 2 h postingestion increased the mRNA expression of β-catenin after 9 days of incubation. We conclude that osteoblast activity and function are increased by dried plum ingestion, which may, in part, explain its beneficial effects on bone health.
Publisher: Springer Science and Business Media LLC
Date: 24-06-2022
DOI: 10.1186/S12891-022-05572-7
Abstract: Lumbar spine pathology is a common feature of lower back and/or lower extremity pain and is associated with observable degenerative changes in the lumbar paraspinal muscles that are associated with poor clinical prognosis. Despite the commonly observed phenotype of muscle degeneration in this patient population, its underlying molecular mechanisms are not well understood. The aim of this study was to investigate the relationships between groups of genes within the atrophic, myogenic, fibrogenic, adipogenic, and inflammatory pathways and multifidus muscle health in in iduals undergoing surgery for lumbar spine pathology. Multifidus muscle biopsies were obtained from patients ( n = 59) undergoing surgery for lumbar spine pathology to analyze 42 genes from relevant adipogenic/metabolic, atrophic, fibrogenic, inflammatory, and myogenic gene pathways using quantitative polymerase chain reaction. Multifidus muscle morphology was examined preoperatively in these patients at the level and side of biopsy using T2-weighted magnetic resonance imaging to determine whole muscle compartment area, lean muscle area, fat cross-sectional areas, and proportion of fat within the muscle compartment. These measures were used to investigate the relationships between gene expression patterns and muscle size and quality. Relationships between gene expression and imaging revealed significant associations between decreased expression of adipogenic/metabolic gene (PPARD), increased expression of fibrogenic gene (COL3A1), and lower fat fraction on MRI ( r = -0.346, p = 0.018, and r = 0.386, p = 0.047 respectively). Decreased expression of myogenic gene (mTOR) was related to greater lean muscle cross-sectional area ( r = 0.388, p = 0.045). Fibrogenic and adipogenic/metabolic genes were related to pre-operative muscle quality, and myogenic genes were related to pre-operative muscle size. These findings provide insight into molecular pathways associated with muscle health in the presence of lumbar spine pathology, establishing a foundation for future research that addresses how these changes impact outcomes in this patient population.
Publisher: American Physiological Society
Date: 11-2009
DOI: 10.1152/AJPENDO.00158.2009
Abstract: The transcription factor TORC2 [transducer of regulated cAMP-responsive element-binding protein (CREB) activity 2] is a major regulator of hepatic gluconeogenesis and is increased in hyperglycemic rodent models. Because chronic hyperglycemia and increased hepatic glucose production, via increased gluconeogenesis, is a key feature of type 2 diabetes, an effective in vivo method to efficiently knock down TORC2 could provide a potential therapy for treating hyperglycemia and type 2 diabetes. To assess this, primary mouse hepatocytes, high-fat diet (HFD)-fed mice, and Zucker diabetic fatty (ZDF) rats were treated with a siRNA against TORC2 (siTORC2), which was delivered via a novel lipid nanoparticle system, or control siRNA (siCON). Compared with siCON, administration of siTORC2 resulted in highly efficient, sustained (1–3 wk) knockdown of TORC2 and its gluconeogenic target genes phospho enolpyruvate carboxykinase and glucose-6-phophatase in primary mouse hepatocytes and in the livers of HFD-fed mice. In mice, this knockdown was specific to the liver and did not occur in kidney, skeletal muscle, or adipose tissue. In HFD-fed mice, siTORC2 reduced in vivo gluconeogenic capacity, fasting hepatic glucose production, and hyperglycemia, and led to improved hepatic and skeletal muscle insulin sensitivity. siTORC2 treatment also improved systemic hyperglycemia in ZDF rats. In conclusion, these results demonstrate the importance of TORC2 in modulating HGP in vivo and highlight a novel, liver-specific siRNA approach for the potential treatment of hyperglycemia and type 2 diabetes.
Publisher: Elsevier BV
Date: 10-2009
Publisher: Wiley
Date: 25-03-2018
DOI: 10.1002/JCP.26542
Abstract: Skeletal muscle fibers are giant multinucleated cells wherein in idual nuclei govern the protein synthesis in a finite volume of cytoplasm this is termed the myonuclear domain (MND). The factors that control MND size remain to be defined. In the present study, we studied the contribution of the NAD + ‐dependent deacetylase, sirtuin 1 (SIRT1), to the regulation of nuclear number and MND size. For this, we isolated myofibers from mice with tissue‐specific inactivation (mKO) or inducible overexpression (imOX) of SIRT1 and analyzed the 3D organisation of myonuclei. In imOX mice, the number of nuclei was increased whilst the average MND size was decreased as compared to littermate controls. Our findings were the opposite in mKO mice. Muscle stem cell (satellite cell) numbers were reduced in mKO muscles, a possible explanation for the lower density of myonuclei in these mice however, no change was observed in imOX mice, suggesting that other factors might also be involved, such as the functional regulation of stem cells/muscle precursors. Interestingly, however, the changes in the MND volume did not impact the force‐generating capacity of muscle fibers. Taken together, our results demonstrate that SIRT1 is a key regulator of MND sizes, although the underlying molecular mechanisms and the cause‐effect relationship between MND and muscle function remain to be fully defined.
Location: United States of America
Start Date: 2021
End Date: 2022
Funder: National Institute of Diabetes and Digestive and Kidney Diseases
View Funded ActivityStart Date: 2021
End Date: 2023
Funder: National Institute on Aging
View Funded ActivityStart Date: 2017
End Date: 2020
Funder: National Institute of Arthritis and Musculoskeletal and Skin Diseases
View Funded ActivityStart Date: 2012
End Date: 2018
Funder: National Institute on Aging
View Funded ActivityStart Date: 2018
End Date: 2020
Funder: National Institute of Arthritis and Musculoskeletal and Skin Diseases
View Funded Activity