ORCID Profile
0000-0002-4500-6233
Current Organisations
Tufts University - Boston Campus
,
US Army Research Institute of Environmental Medicine
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Publisher: The Endocrine Society
Date: 14-06-2017
Abstract: Several studies suggest that neutralizing acid load in the diet with alkali had favorable effects on intermediate markers of musculoskeletal health. We examined whether alkali supplementation with potassium bicarbonate [(KHCO3) 81 mmol/d n = 12] vs placebo (n = 12) for 84 days altered serum microRNAs, potential biomarkers associated with innumerable biological processes including bone and muscle metabolism. Serum microRNAs, urinary net acid excretion (UNAE), urinary N-telopeptide (UNTX), urinary calcium (UCa), urinary nitrogen (UN), glomerular filtration rate, serum procollagen type 1 amino-terminal propeptide (P1NP), serum insulin-like growth factor-1 (IGF-1), and its serum binding protein IGFBP3 were measured at baseline and day 84. Baseline characteristics and measurements were similar in the two treatment groups. Eighty-four–day changes in UNAE differed by group (KHCO3, −47 ± 9 mmol placebo, −5 ± 5 mmol P & 0.01). KHCO3 significantly reduced UNTX, UCa, and serum P1NP but did not affect UN, serum IGF-1, or IGFBP3 levels compared with placebo over 84 days. Fold change in serum circulating microRNA (c-miR)-133b differed significantly by group (KHCO3, 2.26 ± 0.85 placebo, −1.23 ± 0.69 P & 0.01) there was a similar trend in c-miR-21-5p. Fold changes in c-miR-133b and c-miR-21-5p were inversely associated with changes in UNAE and UNTX fold change in c-miR-21-5p was inversely associated with change in UCa, with a similar trend with c-miR-133b. In summary, reducing renal acid load with KHCO3 was associated with increased expressions of c-miR-133b and c-miR-21-5p. Furthermore, increases in c-miRNA-133b and c-miR-21-5p were inversely associated with bone resorption markers UNTX and UCa consistent with potential beneficial effects on bone in older adults. However, the broader significance of c-miRNAs as musculoskeletal biomarkers is still under investigation, and larger studies are needed to verify these preliminary results.
Publisher: Springer Science and Business Media LLC
Date: 11-05-2013
Publisher: Canadian Science Publishing
Date: 10-2009
DOI: 10.1139/H09-073
Abstract: The mammalian target of rapamycin (mTOR) is a highly conserved atypical serine–threonine kinase that controls numerous functions essential for cell homeostasis and adaptation in mammalian cells via 2 distinct protein complex formations. Moreover, mTOR is a key regulatory protein in the insulin signalling cascade and has also been characterized as an insulin-independent nutrient sensor that may represent a critical mediator in obesity-related impairments of insulin action in skeletal muscle. Exercise characterizes a remedial modality that enhances mTOR activity and subsequently promotes beneficial metabolic adaptation in skeletal muscle. Thus, the metabolic effects of nutrients and exercise have the capacity to converge at the mTOR protein complexes and subsequently modify mTOR function. Accordingly, the aim of the present review is to highlight the role of mTOR in the regulation of insulin action in response to overnutrition and the capacity for exercise to enhance mTOR activity in skeletal muscle.
Publisher: Wiley
Date: 30-03-2005
Publisher: Wiley
Date: 13-06-2014
DOI: 10.1096/FJ.14-254490
Publisher: American Physiological Society
Date: 04-2011
DOI: 10.1152/AJPREGU.00659.2010
Abstract: Chronic metabolic diseases develop from the complex interaction of environmental and genetic factors, although the extent to which each contributes to these disorders is unknown. Here, we test the hypothesis that artificial selection for low intrinsic aerobic running capacity is associated with reduced skeletal muscle metabolism and impaired metabolic health. Rat models for low- (LCR) and high- (HCR) intrinsic running capacity were derived from genetically heterogeneous N:NIH stock for 20 generations. Artificial selection produced a 530% difference in running capacity between LCR/HCR, which was associated with significant functional differences in glucose and lipid handling by skeletal muscle, as assessed by hindlimb perfusion. LCR had reduced rates of skeletal muscle glucose uptake (∼30% P = 0.04), glucose oxidation (∼50% P = 0.04), and lipid oxidation (∼40% P = 0.02). Artificial selection for low aerobic capacity was also linked with reduced molecular signaling, decreased muscle glycogen, and triglyceride storage, and a lower mitochondrial content in skeletal muscle, with the most profound changes to these parameters evident in white rather than red muscle. We show that a low intrinsic aerobic running capacity confers reduced insulin sensitivity in skeletal muscle and is associated with impaired markers of metabolic health compared with high intrinsic running capacity. Furthermore, selection for high running capacity, in the absence of exercise training, endows increased skeletal muscle insulin sensitivity and oxidative capacity in specifically white muscle rather than red muscle. These data provide evidence that differences in white muscle may have a role in the ergent aerobic capacity observed in this generation of LCR/HCR.
Publisher: Elsevier BV
Date: 06-2017
Publisher: American Physiological Society
Date: 09-2017
DOI: 10.1152/AJPREGU.00054.2017
Abstract: The objective of the present investigation was to determine whether energy restriction (ER) influences expression of skeletal muscle-specific microRNA (miRNA) in circulation (c-myomiR) and whether changes in c-myomiR are associated with rates of whole body protein synthesis. Sixteen older (64 ± 2 yr) overweight (28.5 ± 1.2 kg/m 2 ) men enrolled in this 35-day controlled feeding trial. A 7-day weight maintenance (WM) period was followed by 28 days of 30% ER. Whole body protein turnover was determined from [ 15 N]glycine enrichments in 24-h urine collections, and c-myomiR (miR-1-3p, miR-133a-3p, miR-133b, and miR-206) expression was assessed from serum s les by RT-quantitative PCR upon completion of the WM and ER periods. Participants lost 4.4 ± 0.3 kg body mass during ER ( P 0.05). After 28 days of ER, miR-133a and miR-133b expression was upregulated ( P 0.05) compared with WM. When all four c-myomiR were grouped as c-myomiR score (sum of the median fold change of all myomiR), overall expression of c-myomiR was higher ( P 0.05) at ER than WM. Backward linear regression analysis of whole body protein synthesis and breakdown and carbohydrate, fat, and protein oxidation determined protein synthesis to be the strongest predictor of c-myomiR score. An inverse association ( P 0.05) was observed with ER c-myomiR score and whole body protein synthesis ( r = −0.729, r 2 = −0.530). Findings from the present investigation provide evidence that upregulation of c-myomiR expression profiles in response to short-term ER is associated with lower rates of whole body protein synthesis.
Publisher: American Diabetes Association
Date: 17-07-2013
DOI: 10.2337/DB13-0062
Abstract: Low aerobic exercise capacity is a risk factor for diabetes and a strong predictor of mortality, yet some in iduals are “exercise-resistant” and unable to improve exercise capacity through exercise training. To test the hypothesis that resistance to aerobic exercise training underlies metabolic disease risk, we used selective breeding for 15 generations to develop rat models of low and high aerobic response to training. Before exercise training, rats selected as low and high responders had similar exercise capacities. However, after 8 weeks of treadmill training, low responders failed to improve their exercise capacity, whereas high responders improved by 54%. Remarkably, low responders to aerobic training exhibited pronounced metabolic dysfunction characterized by insulin resistance and increased adiposity, demonstrating that the exercise-resistant phenotype segregates with disease risk. Low responders had impaired exercise-induced angiogenesis in muscle however, mitochondrial capacity was intact and increased normally with exercise training, demonstrating that mitochondria are not limiting for aerobic adaptation or responsible for metabolic dysfunction in low responders. Low responders had increased stress/inflammatory signaling and altered transforming growth factor-β signaling, characterized by hyperphosphorylation of a novel exercise-regulated phosphorylation site on SMAD2. Using this powerful biological model system, we have discovered key pathways for low exercise training response that may represent novel targets for the treatment of metabolic disease.
Publisher: The Endocrine Society
Date: 12-2013
DOI: 10.1210/JC.2013-2820
Publisher: Elsevier BV
Date: 06-2021
DOI: 10.1016/J.CYTO.2021.155494
Abstract: Interleukin-6 (IL-6) is associated with pathological cardiac hypertrophy and can be dramatically increased in serum after an acute strenuous exercise session. However, IL-6 is also associated with the increased production and release of anti-inflammatory cytokines and the inhibition of tumor necrosis factor-alpha (TNF-α) after chronic moderate exercise. To elucidate the relevance of IL-6 in inflammatory and hypertrophic signaling in the heart in response to an acute strenuous exercise session, we combined transcriptome analysis using the BXD mice database and exercised IL-6 knockout mice (IL-6KO). Bioinformatic analysis demonstrated that low or high-levels of Il6 mRNA in the heart did not change the inflammation- and hypertrophy-related genes in BXD mice strains. On the other hand, bioinformatic analysis revealed a strong positive correlation between Il6 gene expression in skeletal muscle with inflammation-related genes in cardiac tissue in several BXD mouse strains, suggesting that skeletal muscle-derived IL-6 could alter the heart's intracellular signals, particularly the inflammatory signaling. As expected, an acute strenuous exercise session increased IL-6 levels in wild-type, but not in IL-6KO mice. Despite not showing morphofunctional differences in the heart at rest, the IL-6KO group presented a reduction in physical performance and attenuated IL-6, TNF-α, and IL-1beta kinetics in serum, as well as lower p38MAPK phosphorylation, Ampkalpha expression, and higher Acta1 and Tnf gene expressions in the left ventricle in the basal condition. In response to strenuous exercise, IL-6 ablation was linked to a reduction in the pro-inflammatory response and higher activation of classical physiological cardiac hypertrophy proteins.
Publisher: Elsevier BV
Date: 02-2006
DOI: 10.1016/J.METABOL.2005.08.013
Abstract: The aim of this investigation was to determine whether the CAP (Cbl-associated protein)/Cbl signaling cascade is present and responsive to insulin in skeletal muscle and if high-fat feeding impairs insulin-stimulated activation of this signaling cascade. Sprague-Dawley rats were assigned to either control (n = 16) or high fat-fed (n = 16) dietary groups. After a 12-week dietary period, animals were subjected to hind limb perfusions in the presence (n = 8 per group) or absence (n = 8 per group) of insulin. High-fat feeding reduced rates of insulin-stimulated skeletal muscle phosphatidylinositol 3-kinase activity and 3-O-methylglucose transport. In plasma membrane fractions, neither the high-fat diet nor insulin altered the insulin receptor beta subunit (IR-beta), APS (adaptor protein containing PH and SH2 domains), c-Cbl, or TC10 protein concentration, but high-fat feeding did decrease CAP protein concentration. APS, c-Cbl, CAP, and TC10 messenger RNA were present in the skeletal muscle and reflected the protein concentration of experimental groups. Despite insulin-stimulated plasma membrane IR-beta tyrosine phosphorylation being unaffected by high-fat feeding, c-Cbl tyrosine phosphorylation, the kinase activity of IR-beta toward APS, and glucose transporter 4 protein concentration were all significantly reduced in insulin-stimulated plasma membrane prepared from the skeletal muscle of high fat-fed animals. These findings suggest that the CAP/Cbl signaling cascade is present in skeletal muscle, activated by insulin, and impaired by high-fat feeding.
Publisher: Elsevier BV
Date: 09-2008
Publisher: Springer Science and Business Media LLC
Date: 16-11-2022
DOI: 10.1007/S00774-022-01374-Y
Abstract: This study sought to examine the effect of vitamin D It was conducted on a subset of the VD Baseline mean ± SD age was 61 ± 4 years and serum 25-hydroxyvitamin D (25OHD) level was 55.1 ± 22.8 nmol/L. Baseline characteristics did not differ significantly by group. Six-month mean ± SD 25OHD levels were 138.7 ± 22.2 nmol/L (VD This study demonstrated no significant change in intramyonuclear VDR in response to either form of vitamin D vs. placebo. Type I FCSA significantly increased with VD NCT02527668.
Publisher: American Society for Clinical Investigation
Date: 21-12-2015
DOI: 10.1172/JCI79197
Publisher: American Diabetes Association
Date: 07-2007
DOI: 10.2337/DB06-1065
Abstract: Both pharmacological intervention (i.e., thiazolidinediones [TZDs]) and lifestyle modification (i.e., exercise training) are clinically effective treatments for improving whole-body insulin sensitivity. However, the mechanism(s) by which these therapies reverse lipid-induced insulin resistance in skeletal muscle is unclear. We determined the effects of 4 weeks of rosiglitazone treatment and exercise training and their combined actions (rosiglitazone treatment and exercise training) on lipid and glucose metabolism in high-fat–fed rats. High-fat feeding resulted in decreased muscle insulin sensitivity, which was associated with increased rates of palmitate uptake and the accumulation of the fatty acid metabolites ceramide and diacylglycerol. Impairments in lipid metabolism were accompanied by defects in the Akt/AS160 signaling pathway. Exercise training, but not rosiglitazone treatment, reversed these impairments, resulting in improved insulin-stimulated glucose transport and increased rates of fatty acid oxidation in skeletal muscle. The improvements to glucose and lipid metabolism observed with exercise training were associated with increased AMP-activated protein kinase α1 activity increased expression of Akt1, peroxisome proliferator–activated receptor γ coactivator 1, and GLUT4 and a decrease in AS160 expression. In contrast, rosiglitazone treatment exacerbated lipid accumulation and decreased insulin-stimulated glucose transport in skeletal muscle. However, rosiglitazone, but not exercise training, increased adipose tissue GLUT4 and acetyl CoA carboxylase expression. Both exercise training and rosiglitazone decreased liver triacylglycerol content. Although both interventions can improve whole-body insulin sensitivity, our results show that they produce ergent effects on protein expression and triglyceride storage in different tissues. Accordingly, exercise training and rosiglitazone may act as complementary therapies for the treatment of insulin resistance.
Publisher: The Endocrine Society
Date: 09-10-2009
DOI: 10.1210/EN.2009-0158
Abstract: Rats selectively bred for high endurance running capacity (HCR) have higher insulin sensitivity and improved metabolic health compared with those bred for low endurance capacity (LCR). We investigated several skeletal muscle characteristics, in vitro and in vivo, that could contribute to the metabolic phenotypes observed in sedentary LCR and HCR rats. After 16 generations of selective breeding, HCR had approximately 400% higher running capacity (P & 0.001), improved insulin sensitivity (P & 0.001), and lower fasting plasma glucose and triglycerides (P & 0.05) compared with LCR. Skeletal muscle ceramide and diacylglycerol content, basal AMP-activated protein kinase (AMPK) activity, and basal lipolysis were similar between LCR and HCR. However, the stimulation of lipolysis in response to 10 μm isoproterenol was 70% higher in HCR (P = 0.004). Impaired isoproterenol sensitivity in LCR was associated with lower basal triacylglycerol lipase activity, Ser660 phosphorylation of HSL, and β2-adrenergic receptor protein content in skeletal muscle. Expression of the orphan nuclear receptor Nur77, which is induced by β-adrenergic signaling and is associated with insulin sensitivity, was lower in LCR (P & 0.05). Muscle protein content of Nur77 target genes, including uncoupling protein 3, fatty acid translocase/CD36, and the AMPK γ3 subunit were also lower in LCR (P & 0.05). Our investigation associates whole-body insulin resistance with impaired β-adrenergic response and reduced expression of genes that are critical regulators of glucose and lipid metabolism in skeletal muscle. We identify impaired β-adrenergic signal transduction as a potential mechanism for impaired metabolic health after artificial selection for low intrinsic exercise capacity.
Publisher: American Physiological Society
Date: 08-2013
DOI: 10.1152/AJPENDO.00544.2012
Abstract: Impaired visceral white adipose tissue (WAT) metabolism has been implicated in the pathogenesis of several lifestyle-related disease states, with diminished expression of several WAT mitochondrial genes reported in both insulin-resistant humans and rodents. We have used rat models selectively bred for low- (LCR) or high-intrinsic running capacity (HCR) that present simultaneously with ergent metabolic phenotypes to test the hypothesis that oxidative enzyme expression is reduced in epididymal WAT from LCR animals. Based on this assumption, we further hypothesized that short-term exercise training (6 wk of treadmill running) would ameliorate this deficit. Approximately 22-wk-old rats (generation 22) were studied. In untrained rats, the abundance of mitochondrial respiratory complexes I–V, citrate synthase (CS), and PGC-1 was similar for both phenotypes, although CS activity was greater than 50% in HCR ( P = 0.09). Exercise training increased CS activity in both phenotypes but did not alter mitochondrial protein content. Training increased the expression and phosphorylation of proteins with roles in β-adrenergic signaling, including β 3 -adrenergic receptor (16% increase in LCR P 0.05), NOR1 (24% decrease in LCR, 21% decrease in HCR P 0.05), phospho-ATGL (25% increase in HCR P 0.05), perilipin (25% increase in HCR P 0.05), CGI-58 (15% increase in LCR P 0.05), and GLUT4 (16% increase in HCR P 0.0001). A training effect was also observed for phospho-p38 MAPK (12% decrease in LCR, 20% decrease in HCR P 0.05) and phospho-JNK (29% increase in LCR, 20% increase in HCR P 0.05). We conclude that in the LCR-HCR model system, mitochondrial protein expression in WAT is not affected by intrinsic running capacity or exercise training. However, training does induce alterations in the activity and expression of several proteins that are essential to the intracellular regulation of WAT metabolism.
Publisher: MDPI AG
Date: 16-05-2018
DOI: 10.3390/NU10050624
Publisher: American Physiological Society
Date: 12-2012
DOI: 10.1152/JAPPLPHYSIOL.00412.2012
Abstract: One of the most fundamental adaptive physiological events is the response of skeletal muscle to high-intensity resistance exercise, resulting in increased protein synthesis and ultimately larger muscle mass. However, muscle growth in response to contraction is attenuated in older humans. Impaired contractile-induced muscle growth may contribute to sarcopenia: the age-associated loss of muscle mass and function that is manifested by loss of strength, contractile capacity, and endurance. We hypothesized that the storage of ceramide would be increased in older in iduals and this would be associated with increases in NFκB signaling and a decreased anabolic response to exercise. To test this hypothesis we measured ceramides at rest and anabolic and NFκB signaling after an acute bout of high-intensity resistance exercise in young and older males. Using lipidomics analysis we show there was a 156% increase in the accumulation of C16:0-ceramide ( P 0.05) and a 30% increase in C20:0-ceramide ( P 0.05) in skeletal muscle with aging, although there was no observable difference in total ceramide. C16:0-ceramide content was negatively correlated ( P = 0.008) with lower leg lean mass. Aging was associated with a ∼60% increase in the phosphorylation of the proinflammatory transcription factor NFκB in the total and nuclear cell fractions ( P 0.05). Furthermore, there was an attenuated activation of anabolic signaling molecules such as Akt ( P 0.05), FOXO1 ( P 0.05), and S6K1 ( P 0.05) after an acute bout of high-intensity resistance exercise in older males. We conclude that ceramide may have a significant role in the attenuation of contractile-induced skeletal muscle adaptations and atrophy that is observed with aging.
Publisher: Springer Science and Business Media LLC
Date: 21-11-2022
DOI: 10.1038/S41598-022-24277-4
Abstract: The transcriptional repressor REV-ERB-α, encoded by Nuclear Receptor Subfamily 1 Group D Member 1 ( Nr1d1 ), has been considered to play an essential role in the skeletal muscle oxidative capacity adaptation and muscle mass control. Also, this molecule regulates autophagy via the repression of autophagy-related genes both in skeletal muscle and brain regions. Classically, training programs based on endurance or strength characteristics enhance skeletal muscle mass content and/or oxidative capacity, leading to autophagy activation in several tissues. Thus, it seems that REV-ERB-α regulates similar responses induced by exercise. However, how this molecule responds to different exercise models/intensities in different tissues is still unclear. Therefore, the main aim was to characterize the responses of REV-ERB-α and autophagy-related genes to different exercise protocols (endurance/interval run/strength) in distinct tissues (gastrocnemius, soleus and hippoc us). Since REV-ERB-α presents a circadian rhythm, the analyses were performed in a time-course manner. The endurance and strength groups attenuated REV-ERB-α transcriptional response during the time course in gastrocnemius and soleus. Conversely, the interval group enhanced the Nr1d1 expression in the hippoc us. All protocols downregulated the REV-ERB-α protein levels in gastrocnemius following the exercise session with concomitant nuclear exclusion. The major autophagy-related genes presented downregulation after the exercise session in all analyzed tissues. Altogether, these results highlight that REV-ERB-α is extremely sensitive to physical exercise stimuli, including different models and intensities in skeletal muscle and the hippoc us.
Publisher: Frontiers Media SA
Date: 13-10-2022
DOI: 10.3389/FIMMU.2022.953272
Abstract: Interleukin 6 (IL-6) acts as a pro and anti-inflammatory cytokine, has an intense correlation with exercise intensity, and activates various pathways such as autophagy and mitochondrial unfolded protein response. Also, IL-6 is interconnected to circadian clock-related inflammation and can be suppressed by the nuclear receptor subfamily 1, group D, member 1 ( Nr1d1 , protein product REV-ERBα). Since IL-6 is linked to physical exercise-modulated metabolic pathways such as autophagy and mitochondrial metabolism, we investigated the relationship of IL-6 with REV-ERBα in the adaptations of these molecular pathways in response to acute intense physical exercise in skeletal muscle. The present study was ided into three experiments. In the first one, wild-type (WT) and IL-6 knockout (IL-6 KO) mice were ided into three groups: Basal time (Basal sacrificed before the acute exercise), 1 hour (1hr post-Ex sacrificed 1 hour after the acute exercise), and 3 hours (3hr post-Ex sacrificed 3 hours after the acute exercise). In the second experiment, C2C12 cells received IL-6 physiological concentrations or REV-ERBα agonist, SR9009. In the last experiment, WT mice received SR9009 injections. After the protocols, the gastrocnemius muscle or the cells were collected for reverse transcription-quantitative polymerase chain reaction (RTq-PCR) and immunoblotting techniques. In summary, the downregulation of REV-ERBα, autophagic flux, and most mitochondrial genes was verified in the IL-6 KO mice independent of exercise. The WT and IL-6 KO treated with SR9009 showed an upregulation of autophagic genes. C2C12 cells receiving IL-6 did not modulate the Nr1d1 mRNA levels but upregulated the expression of some mitochondrial genes. However, when treated with SR9009, IL-6 and mitochondrial gene expression were upregulated in C2C12 cells. The autophagic flux in C2C12 suggest the participation of REV-ERBα protein in the IL-6-induced autophagy. In conclusion, the present study verified that the adaptations required through physical exercise (increases in mitochondrial content and improvement of autophagy machinery) might be intermediated by an interaction between IL-6 and REVERBα.
Publisher: American Physiological Society
Date: 10-2007
DOI: 10.1152/AJPENDO.00230.2007
Abstract: The aims of this investigation were 1) to determine whether endurance exercise training could reverse impairments in insulin-stimulated compartmentalization and/or activation of aPKCζ/λ and Akt2 in skeletal muscle from high-fat-fed rodents and 2) to assess whether the PPARγ agonist rosiglitazone could reverse impairments in skeletal muscle insulin signaling typically observed after high-fat feeding. Sprague-Dawley rats were placed on chow (NORCON, n = 16) or high-fat ( n = 64) diets for 4 wk. During a subsequent 4-wk experimental period, high-fat-fed rats were allocated ( n = 16/group) to either sedentary control (HFC), exercise training (HFX), rosiglitazone treatment (HFRSG), or a combination of both exercise training and rosiglitazone (HFRX). Following the 4-wk experimental period, animals underwent hindlimb perfusions. Insulin-stimulated plasma membrane-associated aPKCζ and -λ protein concentration, aPKCζ/λ activity, GLUT4 protein concentration, cytosolic Akt2, and aPKCζ/λ activities were reduced ( P 0.05) in HFC compared with NORCON. Cytosolic Akt2, aPKCζ, and aPKCλ protein concentrations were not affected in HFC compared with NORCON. Exercise training reversed the deleterious effects of the high-fat diet such that insulin-stimulated compartmentalization and activation of components of the insulin-signaling cascade in HFX were normalized to NORCON. High-fat diet-induced impairments to skeletal muscle glucose metabolism were not reversed by rosiglitazone administration, nor did rosiglitazone augment the effect of exercise. Our findings indicate that chronic exercise training, but not rosiglitazone, reverses high-fat diet induced impairments in compartmentalization and activation of components of the insulin-signaling cascade in skeletal muscle.
Publisher: Springer Science and Business Media LLC
Date: 15-07-2022
Publisher: MDPI AG
Date: 09-11-2021
DOI: 10.3390/NU13113985
Abstract: The primary objective of this study was to investigate the potential synergy between low doses of L-carnitine tartrate and creatine monohydrate to induce muscle protein synthesis and anabolic pathway activation in primary human myoblasts. In addition, the effects of Lipid multi-particulates (LMP) formulation on creatine stability and bioavailability were assessed in rodents and healthy human subjects. When used in idually, L-carnitine tartrate at 50 µM and creatine monohydrate at 0.5 µM did not affect myoblast protein synthesis and signaling. However, when combined, they led to a significant increase in protein synthesis. Increased AKT and RPS6 phosphorylation were observed with 50 µM L-carnitine tartrate 5 µM creatine in combination in primary human myoblasts. When Wistar rats were administered creatine with LMP formulation at either 21 or 51 mg/kg, bioavailability was increased by 27% based on the increase in the area under the curve (AUC) at a 51 mg/kg dose compared to without LMP formulation. Tmax and Cmax were unchanged. Finally, in human subjects, a combination of LMP formulated L-carnitine at 500 mg (from L-carnitine tartrate) with LMP formulated creatine at 100, 200, or 500 mg revealed a significant and dose-dependent increase in plasma creatine concentrations. Serum total L-carnitine levels rose in a similar manner in the three combinations. These results suggest that a combination of low doses of L-carnitine tartrate and creatine monohydrate may lead to a significant and synergistic enhancement of muscle protein synthesis and activation of anabolic signaling. In addition, the LMP formulation of creatine improved its bioavailability. L-carnitine at 500 mg and LMP-formulated creatine at 200 or 500 mg may be useful for future clinical trials to evaluate the effects on muscle protein synthesis.
Publisher: American Physiological Society
Date: 04-2016
DOI: 10.1152/AJPREGU.00198.2015
Abstract: The loss of skeletal muscle mass is observed in many pathophysiological conditions, including aging and obesity. The loss of muscle mass and function with aging is defined as sarcopenia and is characterized by a mismatch between skeletal muscle protein synthesis and breakdown. Characteristic metabolic features of both aging and obesity are increases in intramyocellular lipid (IMCL) content in muscle. IMCL accumulation may play a mechanistic role in the development of anabolic resistance and the progression of muscle atrophy in aging and obesity. In the present study, aged and high-fat fed mice were used to determine mechanisms leading to muscle loss. We hypothesized the accumulation of bioactive lipids in skeletal muscle, such as ceramide or diacylglycerols, leads to insulin resistance with aging and obesity and the inability to activate protein synthesis, contributing to skeletal muscle loss. We report a positive association between bioactive lipid accumulation and the loss of lean mass and muscle strength. Obese and aged animals had significantly higher storage of ceramide and diacylglycerol compared with young. Furthermore, there was an attenuated insulin response in components of the mTOR anabolic signaling pathway. We also observed differential increases in the expression of inflammatory cytokines and the phosphorylation of IκBα with aging and obesity. These data challenge the accepted role of increased inflammation in obesity-induced insulin resistance in skeletal muscle. Furthermore, we have now established IκBα with a novel function in aging-associated muscle loss that may be independent of its previously understood role as an NF-κB inhibitor.
Publisher: Bioscientifica
Date: 02-07-2009
DOI: 10.1677/JOE-09-0202
Abstract: The serine/threonine protein kinase, mammalian target of rapamycin (mTOR) is regulated by insulin and nutrient availability and has been proposed to play a central role as a nutrient sensor in skeletal muscle. mTOR associates with its binding partners, raptor and rictor, to form two structurally and functionally distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) respectively. We have investigated the assembly of mTORC1/2 and the activation of their downstream substrates (i.e. Akt, S6K1) in response to known effectors of mTOR, excess lipid availability and AMP-activated protein kinase (AMPK) activation/exercise training in rat skeletal muscle. The in vivo formation of mTORC1 and 2 and the activation of their respective downstream substrates were increased in response to chronic (8 weeks) consumption of a high-fat diet. Diet-induced mTORC activation and skeletal muscle insulin resistance were reversed by 4 weeks of exercise training, which was associated with enhanced muscle AMPK activation. In order to determine whether AMPK activation reverses lipid-induced mTOR activation, L6 myotubes were exposed to 0.4 mM palmitate to activate mTORC1/2 in the absence or presence of 5′-aminoimidazole-4-carboxamide-1-β- d -ribofuranoside (AICAR). Palmitate exposure (4 h) increased insulin-stimulated S6K1 Thr389 phosphorylation by 60%, indicating activation of mTORC1. AMPK activation with 1 mM AICAR abolished lipid-induced mTOR activation in vitro . Our data implicates reductions in mTOR complex activation with the reversal of lipid-induced skeletal muscle insulin resistance in response to exercise training or AICAR and identifies mTOR as a potential target for the treatment of insulin resistance.
Publisher: American Physiological Society
Date: 09-2019
DOI: 10.1152/AJPCELL.00455.2018
Abstract: Sarcopenia, the age-associated loss of skeletal muscle mass and function, is coupled with declines in physical functioning leading to subsequent higher rates of disability, frailty, morbidity, and mortality. Aging and obesity independently contribute to muscle atrophy that is assumed to be a result of the activation of mutual physiological pathways. Understanding mechanisms contributing to the induction of skeletal muscle atrophy with aging and obesity is important for determining targets that may have pivotal roles in muscle loss in these conditions. We find that aging and obesity equally induce an anabolic resistance to acute skeletal muscle contraction as observed with decreases in anabolic signaling activation after contraction. Furthermore, treatment with the sphingosine-1-phosphate analog FTY720 for 4 wk increased lean mass and strength, and the anabolic signaling response to contraction was improved in obese but not older animals. To determine the role of chronic inflammation and different fatty acids on anabolic resistance in skeletal muscle cells, we overexpressed IKKβ with and without exposure to saturated fatty acid (SFA palmitic acid), polyunsaturated fatty acid (eicosapentaenoic acid), and monounsaturated fatty acid (oleic acid). We found that IKKβ overexpression increased inflammation markers in muscle cells, and this chronic inflammation exacerbated anabolic resistance in response to SFA. Pretreatment with FTY720 reversed the inflammatory effects of palmitic acid in the muscle cells. Taken together, these data demonstrate chronic inflammation can induce anabolic resistance, SFA aggravates these effects, and FTY720 can reverse this by decreasing ceramide accumulation in skeletal muscle.
Publisher: Springer Netherlands
Date: 18-11-2010
Publisher: Wiley
Date: 22-04-2011
Publisher: Springer Science and Business Media LLC
Date: 02-07-2010
Publisher: Springer Science and Business Media LLC
Date: 02-08-2018
DOI: 10.1038/S41467-018-05439-3
Abstract: Skeletal muscle has a remarkable plasticity to adapt and remodel in response to environmental cues, such as physical exercise. Endurance exercise stimulates improvements in muscle oxidative capacity, while resistance exercise induces muscle growth. Here we show that the c-Jun N-terminal kinase (JNK) is a molecular switch that when active, stimulates muscle fibers to grow, resulting in increased muscle mass. Conversely, when muscle JNK activation is suppressed, an alternative remodeling program is initiated, resulting in smaller, more oxidative muscle fibers, and enhanced aerobic fitness. When muscle is exposed to mechanical stress, JNK initiates muscle growth via phosphorylation of the transcription factor, SMAD2, at specific linker region residues leading to inhibition of the growth suppressor, myostatin. In human skeletal muscle, this JNK/SMAD signaling axis is activated by resistance exercise, but not endurance exercise. We conclude that JNK acts as a key mediator of muscle remodeling during exercise via regulation of myostatin/SMAD signaling.
Publisher: Wiley
Date: 06-2005
Publisher: Elsevier BV
Date: 2023
DOI: 10.1016/J.LFS.2022.121175
Abstract: Aging can modify the morphology and function of the liver, such as generating a decrease in the mitochondria content, autophagy, and cell senescence. Although exercise training has several beneficial effects on hepatic metabolism, its actions on autophagy processes, mitochondrial function, and cellular senescence need to be more widely explored. The present study verified the effects of aging and exercise on hepatic circadian markers, autophagy, and mitochondria activity in 24-month-old mice with a combined exercise training protocol. In addition, we used public datasets from human livers in several conditions and BMAL1 knockout mice. C57BL/6 mice were distributed into Control (CT, young, 6-month-old mice), sedentary old (Old Sed, sedentary, 24-month-old mice), and exercised old (Old Ex, 24-month-old mice submitted to a combined exercise training protocol). The exercise training protocol consisted of three days of endurance exercise - treadmill running, and two days of resistance exercise - climbing a ladder, for three weeks. At the end of the protocol, the liver was removed and prepared for histological analysis, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), immunoblotting technique, and oxygen consumption. Heatmaps were built using a human dataset and Bmal1 knockout s les. In summary, the Old Sed had reduced strength, coordination, and balance, as well as a decrease in Bmal1 expression and the presence of degenerated liver cells. Still, this group upregulated the transcription factors related to mitochondrial biogenesis. The Old Ex group had increased strength, coordination, and balance, improved glucose sensitivity, as well as restored Bmal1 expression and the mitochondrial transcription factors. The human datasets indicated that mitochondrial markers and autophagy strongly correlate with specific liver diseases but not aging. We can speculate that mitochondrial and autophagy molecular markers alterations may depend on long-term training.
Publisher: American Physiological Society
Date: 12-2021
DOI: 10.1152/AJPCELL.00190.2021
Abstract: Understanding paradoxical responses to anabolic stimulation and identifying the mechanisms for this inconsistency in mobility-limited older adults may provide new targets for the treatment of sarcopenia. Our laboratory has discovered that dysregulation in microRNA (miRNA) that target anabolic pathways is a potential mechanism resulting in age-associated decreases in skeletal muscle mass and function (sarcopenia). The objective of the current study was to assess circulating miRNA expression profiles in diametric response of leg lean mass in mobility-limited older in iduals after a 6-mo progressive resistance exercise training intervention (PRET) and determine the influence of differentially expressing miRNA on regulation of skeletal muscle mass. Participants were dichotomized by gain (Gainers mean +561.4 g, n = 33) or loss (Losers mean −589.8 g, n = 40) of leg lean mass after PRET. Gainers significantly increased fat-free mass 2.4% vs. −0.4% for Losers. Six miRNA (miR-1-3p, miR-19b-3p, miR-92a, miR-126, miR-133a-3p, and miR-133b) were significantly identified to be differentially expressed between Gainers and Losers, with miR-19b-3p being the miRNA most highly associated with increases in fat-free mass. Using an aging mouse model, we then assessed if miR-19b-3p expression was different in young mice with larger muscle mass compared with older mice. Circulating and skeletal muscle miR-19b-3p expression was higher in young compared with old mice and was positively associated with muscle mass and grip strength. We then used a novel integrative approach to determine if differences in circulating miR-19b-3p potentially translate to augmented anabolic response in human skeletal muscle cells in vitro. Results from this analysis identified that overexpression of miR-19b-3p targeted and downregulated PTEN by 64% to facilitate significant ∼50% increase in muscle protein synthetic rate as measured with SUnSET. The combine results of these three models identify miR-19b-3p as a potent regulator of muscle anabolism that may contribute to an inter-in idual response to PRET in mobility-limited older adults.
Publisher: The Company of Biologists
Date: 15-01-2009
DOI: 10.1242/JEB.025296
Abstract: To examine the evolution of endurance-exercise behaviour, we have selectively bred four replicate lines of laboratory mice (Mus domesticus) for high voluntary wheel running (`high runner' or HR lines),while also maintaining four non-selected control (C) lines. By generation 16,HR mice ran ∼2.7-fold more than C mice, mainly by running faster(especially in females), a differential maintained through subsequent generations, suggesting an evolutionary limit of unknown origin. We hypothesized that HR mice would have higher glycogen levels before nightly running, show greater depletion of those depots during their more intense wheel running, and have increased glycogen synthase activity and GLUT-4 protein in skeletal muscle. We s led females from generation 35 at three times (photophase 07:00 h–19:00 h) during days 5–6 of wheel access, as in the routine selection protocol: Group 1, day 5, 16:00 h–17:30 h, wheels blocked from 13:00 h Group 2, day 6, 02:00 h–03:30 h (immediately after peak running) and Group 3, day 6, 07:00 h–08:30 h. An additional Group 4, s led 16:00 h–17:30 h, never had wheels. HR in iduals with the mini-muscle phenotype (50% reduced hindlimb muscle mass) were distinguished for statistical analyses comparing C,HR normal, and HR mini. HR mini ran more than HR normal, and at higher speeds,which might explain why they have been favored by the selective-breeding protocol. Plasma glucose was higher in Group 1 than in Group 4, indicating a training effect (phenotypic plasticity). Without wheels, no differences in gastrocnemius GLUT-4 were observed. After 5 days with wheels, all mice showed elevated GLUT-4, but HR normal and mini were 2.5-fold higher than C. At all times and irrespective of wheel access, HR mini showed approximately three-fold higher [glycogen] in gastrocnemius and altered glycogen synthase activity. HR mini also showed elevated glycogen in soleus when s led during peak running. All mice showed some glycogen depletion during nightly wheel running, in muscles and/or liver, but the magnitude of this depletion was not large and hence does not seem to be limiting to the evolution of even-higher wheel running.
Publisher: American Physiological Society
Date: 2011
DOI: 10.1152/AJPREGU.00338.2010
Abstract: We have used a novel model of genetically imparted endurance exercise capacity and metabolic health to study the genetic and environmental contributions to skeletal muscle glucose and lipid metabolism. We hypothesized that metabolic abnormalities associated with low intrinsic running capacity would be ameliorated by exercise training. Selective breeding for 22 generations resulted in rat models with a fivefold difference in intrinsic aerobic capacity. Low (LCR)- and high (HCR)-capacity runners remained sedentary (SED) or underwent 6 wk of exercise training (EXT). Insulin-stimulated glucose transport, insulin signal transduction, and rates of palmitate oxidation were lower in LCR SED vs. HCR SED ( P 0.05). Decreases in glucose and lipid metabolism were associated with decreased β 2 -adrenergic receptor (β 2 -AR), and reduced expression of Nur77 target proteins that are critical regulators of muscle glucose and lipid metabolism [uncoupling protein-3 (UCP3), fatty acid transporter (FAT)/CD36 P 0.01 and P 0.05, respectively]. EXT reversed the impairments to glucose and lipid metabolism observed in the skeletal muscle of LCR, while increasing the expression of β 2 -AR, Nur77, GLUT4, UCP3, and FAT/CD36 ( P 0.05) in this tissue. However, no metabolic improvements were observed following exercise training in HCR. Our results demonstrate that metabolic impairments resulting from genetic factors (low intrinsic aerobic capacity) can be overcome by an environmental intervention (exercise training). Furthermore, we identify Nur77 as a potential mechanism for improved skeletal muscle metabolism in response to EXT.
Publisher: American Physiological Society
Date: 11-2022
DOI: 10.1152/AJPENDO.00110.2022
Abstract: Results provide novel insight into effects of carbohydrate intake on the expression of skeletal muscle microRNA during early recovery from aerobic exercise and reveal that Let7i-5p and miR-195-5p are important regulators of skeletal muscle protein breakdown to aid in facilitating muscle recovery.
Publisher: Wiley
Date: 16-05-2012
Publisher: MDPI AG
Date: 10-11-2020
DOI: 10.3390/IJMS21228416
Abstract: The protective effects of chronic moderate exercise-mediated autophagy include the prevention and treatment of several diseases and the extension of lifespan. In addition, physical exercise may impair cellular structures, requiring the action of the autophagy mechanism for clearance and renovation of damaged cellular components. For the first time, we investigated the adaptations on basal autophagy flux in vivo in mice’s liver, heart, and skeletal muscle tissues submitted to four different chronic exercise models: endurance, resistance, concurrent, and overtraining. Measuring the autophagy flux in vivo is crucial to access the functionality of the autophagy pathway since changes in this pathway can occur in more than five steps. Moreover, the responses of metabolic, performance, and functional parameters, as well as genes and proteins related to the autophagy pathway, were addressed. In summary, the regular exercise models exhibited normal/enhanced adaptations with reduced autophagy-related proteins in all tissues. On the other hand, the overtrained group presented higher expression of Sqstm1 and Bnip3 with negative morphological and physical performance adaptations for the liver and heart, respectively. The groups showed different adaptions in autophagy flux in skeletal muscle, suggesting the activation or inhibition of basal autophagy may not always be related to improvement or impairment of performance.
Publisher: American Physiological Society
Date: 03-2013
DOI: 10.1152/AJPHEART.00638.2012
Abstract: Rats selectively bred for low (LCR) or high (HCR) intrinsic running capacity simultaneously present with contrasting risk factors for cardiovascular and metabolic disease. However, the impact of these phenotypes on left ventricular (LV) morphology and microvascular function, and their progression with aging, remains unresolved. We tested the hypothesis that the LCR phenotype induces progressive age-dependent LV remodeling and impairments in microvascular function, glucose utilization, and β-adrenergic responsiveness, compared with HCR. Hearts and vessels isolated from female LCR ( n = 22) or HCR ( n = 26) were studied at 12 and 35 wk. Nonselected N:NIH founder rats (11 wk) were also investigated ( n = 12). LCR had impaired glucose tolerance and elevated plasma insulin (but not glucose) and body-mass at 12 wk compared with HCR, with early LV remodeling. By 35 wk, LV prohypertrophic and glucose transporter GLUT4 gene expression were up- and downregulated, respectively. No differences in LV β-adrenoceptor expression or cAMP content between phenotypes were observed. Macrovascular endothelial function was predominantly nitric oxide (NO)-mediated in both phenotypes and remained intact in LCR for both age-groups. In contrast, mesenteric arteries microvascular endothelial function, which was impaired in LCR rats regardless of age. At 35 wk, endothelial-derived hyperpolarizing factor-mediated relaxation was impaired whereas the NO contribution to relaxation is intact. Furthermore, there was reduced β 2 -adrenoceptor responsiveness in both aorta and mesenteric LCR arteries. In conclusion, diminished intrinsic exercise capacity impairs systemic glucose tolerance and is accompanied by progressive development of LV remodeling. Impaired microvascular perfusion is a likely contributing factor to the cardiac phenotype.
Publisher: American Physiological Society
Date: 11-2008
DOI: 10.1152/JAPPLPHYSIOL.90540.2008
Abstract: We have previously reported that 5 days of a high-fat diet followed by 1 day of high-carbohydrate intake (Fat-adapt) increased rates of fat oxidation and decreased rates of muscle glycogenolysis during submaximal cycling compared with consumption of an isoenergetic high-carbohydrate diet (HCHO) for 6 days (Burke et al. J Appl Physiol 89: 2413–2421, 2000 Stellingwerff et al. Am J Physiol Endocrinol Metab 290: E380–E388, 2006). To determine potential mechanisms underlying shifts in substrate selection, eight trained subjects performed Fat-adapt and HCHO. On day 7, subjects performed 1-h cycling at 70% peak O 2 uptake. Muscle biopsies were taken immediately before and after exercise. Resting muscle glycogen content was similar between treatments, but muscle triglyceride levels were higher after Fat-adapt ( P 0.05). Resting AMPK-α 1 and -α 2 activity was higher after Fat-adapt ( P = 0.02 and P = 0.05, respectively), while the phosphorylation of AMPK's downstream target, acetyl-CoA carboxylase (pACC at Ser 221 ), tended to be elevated after Fat-adapt ( P = 0.09). Both the respiratory exchange ratio ( P 0.01) and muscle glycogen utilization ( P 0.05) were lower during exercise after Fat-adapt. Exercise increased AMPK-α 1 activity after HCHO ( P = 0.03) but not Fat-adapt. Exercise was associated with an increase in pACC at Ser 221 for both dietary treatments ( P 0.05), with postexercise pACC Ser 221 higher after Fat-adapt ( P = 0.02). In conclusion, compared with HCHO, Fat-adapt increased resting muscle triglyceride stores and resting AMPK-α 1 and -α 2 activity. Fat-adapt also resulted in higher rates of whole body fat oxidation, reduced muscle glycogenolysis, and attenuated the exercise-induced rise in AMPK-α 1 and AMPK-α 2 activity compared with HCHO. Our results demonstrate that AMPK-α 1 and AMPK-α 2 activity and fuel selection in skeletal muscle in response to exercise can be manipulated by diet and/or the interactive effects of diet and exercise training.
Location: United States of America
Start Date: 2015
End Date: 2020
Funder: National Institute on Aging
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