ORCID Profile
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Animal Physiology - Cell | Physiology | Epigenetics (incl. Genome Methylation and Epigenomics) | Animal Physiology - Systems | Genetics | Preventive Medicine | Exercise Physiology | Bioinformatics | Cell Development, Proliferation and Death |
Health Related to Ageing | Skeletal System and Disorders (incl. Arthritis) | Expanding Knowledge in the Biological Sciences | Women's Health | Expanding Knowledge in the Medical and Health Sciences
Publisher: Cold Spring Harbor Laboratory
Date: 28-04-2022
DOI: 10.1101/2022.04.27.489477
Abstract: Mitochondria are central to cellular function, particularly in metabolically active tissues such as skeletal muscle. Non-coding RNAs (ncRNAs) typically localise within the nucleus and cytosol but may also translocate to subcellular compartments such as mitochondria. We aimed to investigate the nuclear-encoded ncRNAs that localise within the mitochondria of skeletal muscle cells and tissue. Intact mitochondria were isolated via immunoprecipitation and an enzymatic digestion approach was optimised to remove transcripts located exterior to mitochondria, making it amenable for high-throughput transcriptomic sequencing. Small-RNA sequencing libraries were successfully constructed from as little as 1.8ng mitochondrial RNA input. Small-RNA and whole transcriptome sequencing of mitochondria reveals the enrichment of over 200 miRNAs and 200 lncRNAs that have not previously been observed within skeletal muscle mitochondria. In summary, we describe a novel, powerful sequencing approach applicable to animal and human tissues and cells that reveals the unexpected ersity of nuclear-encoded ncRNA transcripts localised within skeletal muscle mitochondria.
Publisher: Springer Science and Business Media LLC
Date: 07-01-2017
Publisher: Informa UK Limited
Date: 18-05-2022
DOI: 10.1080/17461391.2021.1921854
Abstract: Sex steroids, commonly referred to as sex hormones, are integral to the development and maintenance of the human reproductive system. In addition, male (androgens) and female (estrogens and progestogens) sex hormones promote the development of secondary sex characteristics by targeting a range of other tissues, including skeletal muscle. The role of androgens on skeletal muscle mass, function and metabolism has been well described in males, yet female specific studies are scarce in the literature. This narrative review summarises the available evidence around the mechanistic role of androgens, estrogens and progestogens in female skeletal muscle. An analysis of the literature indicates that sex steroids play important roles in the regulation of female skeletal muscle mass and function. The free fractions of testosterone and progesterone in serum were consistently associated with the regulation of muscle mass, while estrogens may be primarily involved in mediating the muscle contractile function in conjunction with other sex hormones. Muscle strength was however not directly associated with any hormone in isolation when at physiological concentrations. Importantly, recent evidence suggests that intramuscular sex hormone concentrations may be more strongly associated with muscle size and function than circulating forms, providing interesting opportunities for future research. By combining cross-sectional, interventional and mechanical studies, this review aims to provide a broad, multidisciplinary picture of the current knowledge of the effects of sex steroids on skeletal muscle in females, with a focus on the regulation of muscle size and function and an insight into their clinical implications. HighlightsFree testosterone, but not total testosterone, is associated with lean mass but not strength in pre- and post-menopausal females.Progesterone and estrogens may regulate muscle mass and strength, respectively, in females.Intra-muscular steroids may be more closely associated to muscle mass and strength, compared to systemic fractions.
Publisher: MDPI AG
Date: 07-2016
DOI: 10.3390/NU8070404
Publisher: Society for Transparency, Openness, and Replication in Kinesiology
Date: 02-06-2022
DOI: 10.51224/SRXIV.158
Publisher: Frontiers Media SA
Date: 08-02-2016
Publisher: Elsevier BV
Date: 2013
DOI: 10.1016/J.NBD.2012.08.015
Abstract: Skeletal muscle mitochondrial dysfunction is believed to play a role in the progression and severity of amyotrophic lateral sclerosis (ALS). The regulation of transcriptional co-activators involved in mitochondrial biogenesis and function in ALS is not well known. When compared with healthy control subjects, patients with ALS, but not neurogenic disease (ND), had lower levels of skeletal muscle peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) mRNA and protein and estrogen-related receptor-α (ERRα) and mitofusin-2 (Mfn2) mRNA. PGC-1β, nuclear respiratory factor-1 (NRF-1) and Mfn1 mRNA as well as cytochrome C oxidase subunit IV (COXIV) mRNA and protein were lower in patients with ALS and ND. Both patient groups had reductions in citrate synthase and cytochrome c oxidase activity. Similar observations were made in skeletal muscle from transgenic ALS G93A transgenic mice. In vitro, PGC-1α and PGC-1β regulated Mfn1 and Mfn2 in an ERRα-dependent manner. Compared to healthy controls, miRNA 23a, 29b, 206 and 455 were increased in skeletal muscle of ALS patients. miR-23a repressed PGC-1α translation in a 3' UTR dependent manner. Transgenic mice over expressing miR-23a had a reduction in PGC-1α, cytochome-b and COXIV protein levels. These results show that skeletal muscle mitochondrial dysfunction in ALS patients is associated with a reduction in PGC-1α signalling networks involved in mitochondrial biogenesis and function, as well as increases in several miRNAs potentially implicated in skeletal muscle and neuromuscular junction regeneration. As miR-23a negatively regulates PGC-1α signalling, therapeutic inhibition of miR-23a may be a strategy to rescue PGC-1α activity and ameliorate skeletal muscle mitochondrial function in ALS.
Publisher: Wiley
Date: 22-12-2017
DOI: 10.1002/MUS.26039
Abstract: The pathology of amyotrophic lateral sclerosis (ALS) is associated with impaired RNA processing and microRNA (miRNA) dysregulation. Here we investigate the regulation of the members of the miRNA biogenesis pathways and total miRNA levels at different stages of the disease. Muscle, brain, and spinal cord tissue were obtained from presymptomatic, symptomatic, and end-stage superoxide dismutase 1 (SOD1) As the diseases progresses, several genes involved in miRNA biogenesis as well as the miRNA/total RNA (totRNA) ratio increased in the tibialis anterior (TA) muscle but not in the soleus or in neural tissue. We propose that a dysregulation in the miRNA/totRNA ratio in the TA muscle from SOD1
Publisher: American Physiological Society
Date: 12-2020
DOI: 10.1152/AJPENDO.00398.2020
Abstract: Skeletal muscle is sensitive to environmental cues that are first present in utero. Maternal overnutrition is a model of impaired muscle development leading to structural and metabolic dysfunction in adult life. In this study, we investigated the effect of an obesogenic maternal environment on growth and postnatal myogenesis in the offspring. Male C57BL/6J mice born to chow- or high-fat-diet-fed mothers were allocated to four different groups at the end of weaning. For the following 10 wk, half of the pups were maintained on the same diet as their mother and half of the pups were switched to the other diet (chow or high-fat). At 12 wk of age, muscle injury was induced using an intramuscular injection of barium chloride. Seven days later, mice were humanely killed and muscle tissue was harvested. A high-fat maternal diet impaired offspring growth patterns and downregulated satellite cell activation and markers of postnatal myogenesis 7 days after injury without altering the number of newly synthetized fibers over the whole 7-day period. Importantly, a healthy postnatal diet could not reverse any of these effects. In addition, we demonstrated that postnatal myogenesis was associated with a diet-independent upregulation of three miRNAs, mmu-miR-31–5p, mmu-miR-136–5p, and mmu-miR-296–5p. Furthermore, in vitro analysis confirmed the role of these miRNAs in myocyte proliferation. Our findings are the first to demonstrate that maternal overnutrition impairs markers of postnatal myogenesis in the offspring and are particularly relevant to today’s society where the incidence of overweight/obesity in women of childbearing age is increasing.
Publisher: Frontiers Media SA
Date: 16-11-2018
Publisher: Cold Spring Harbor Laboratory
Date: 17-03-2021
DOI: 10.1101/2021.03.16.435733
Abstract: Nearly all human complex traits and diseases exhibit some degree of sex differences, with epigenetics being one of the main contributing factors. Various tissues display sex differences in DNA methylation, however this has not yet been explored in skeletal muscle, despite skeletal muscle being among the tissues with the most transcriptomic sex differences. For the first time, we investigated the effect of sex on autosomal DNA methylation in human skeletal muscle across three independent cohorts (Gene SMART, FUSION, and GSE38291) using a meta-analysis approach, totalling 369 human muscle s les (222 males, 147 females), and integrated this with known sex-biased transcriptomics. We found 10,240 differentially methylated regions (DMRs) at FDR 0.005, 94% of which were hypomethylated in males, and gene set enrichment analysis revealed that differentially methylated genes were involved in muscle contraction and substrate metabolism. We then investigated biological factors underlying DNA methylation sex differences and found that circulating hormones were not associated with differential methylation at sex-biased DNA methylation loci, however these sex-specific loci were enriched for binding sites of hormone-related transcription factors (with top TFs including androgen ( AR ), estrogen ( ESR1 ), and glucocorticoid ( NR3C1 ) receptors). Fibre type proportions were associated with differential methylation across the genome, as well as across 16 % of sex-biased DNA methylation loci (FDR 0.005). Integration of DNA methylomic results with transcriptomic data from the GTEx database and the FUSION cohort revealed 326 autosomal genes that display sex differences at both the epigenome and transcriptome levels. Importantly, transcriptional sex-biased genes were overrepresented among epigenetic sex-biased genes (p-value = 4.6e-13), suggesting differential DNA methylation and gene expression between male and female muscle are functionally linked. Finally, we validated expression of three genes with large effect sizes ( FOXO3A, ALDH1A1 , and GGT7 ) in the Gene SMART cohort with qPCR. GGT7 , involved in antioxidant metabolism, displays male-biased expression as well as lower methylation in males across the three cohorts. In conclusion, we uncovered 8,420 genes that exhibit DNA methylation differences between males and females in human skeletal muscle that may modulate mechanisms controlling muscle metabolism and health. The importance of uncovering biological sex differences and their translation to physiology has become increasingly evident. Using a large-scale meta-analysis of three cohorts, we perform the first comparison of genome-wide skeletal muscle DNA methylation between males and females, and identify thousands of genes that display sex-differential methylation. We then explore intrinsic biological factors that may be underlying the DNA methylation sex differences, such as fibre type proportions and sex hormones. Leveraging the GTEx database, we identify hundreds of genes with both sex-differential expression and DNA methylation in skeletal muscle. We further confirm the sex-biased genes with gene expression data from two cohorts included in the methylation meta-analysis. Our study integrates genomewide sex-biased DNA methylation and expression in skeletal muscle, shedding light on distinct sex differences in skeletal muscle.
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.FREERADBIOMED.2015.10.412
Abstract: It is clear that reactive oxygen species (ROS) produced during skeletal muscle contraction have a regulatory role in skeletal muscle adaptation to endurance exercise. However, there is much controversy in the literature regarding whether attenuation of ROS by antioxidant supplementation can prevent these cellular adaptations. Therefore, the aim of this study was to determine whether vitamin C and E supplementation attenuates performance and cellular adaptations following acute endurance exercise and endurance training. A double-blinded, placebo-controlled randomized control trial was conducted in eleven healthy young males. Participants were matched for peak oxygen consumption (VO 2peak) and randomly allocated to placebo or antioxidant (vitamin C (2 × 500 mg/day) and E (400 IU/day)) groups. Following a four-week supplement loading period, participants completed acute exercise (10 × 4 min cycling at 90% VO 2peak, 2 min active recovery). Vastus lateralis muscle s les were collected pre-, immediately-post- and 3h-post-exercise. Participants then completed four weeks of training (3 days/week) using the aforementioned exercise protocol while continuing supplementation. Following exercise training, participants again completed an acute exercise bout with muscle biopsies. Acute exercise tended to increase skeletal muscle oxidative stress as measured by oxidized glutathione (GSSG) (P=0.058) and F2-isoprostanes (P=0.056), with no significant effect of supplementation. Acute exercise significantly increased mRNA levels of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), mitochondrial transcription factor A (TFAM) and PGC related coactivator (PRC), with no effect of supplementation. Following endurance training, supplementation did not prevent significantly increased VO 2peak, skeletal muscle levels of citrate synthase activity or mRNA or protein abundance of cytochrome oxidase subunit 4 (COX IV) (P<0.05). However, following training, vitamin C and E supplementation significantly attenuated increased skeletal muscle superoxide dismutase (SOD) activity and protein abundance of SOD2 and TFAM. Following acute exercise, supplementation with vitamin C and E did not attenuate skeletal muscle oxidative stress or increased gene expression of mitochondrial biogenesis markers. However, supplementation attenuated some (SOD, TFAM) of the increased skeletal muscle adaptations following training in healthy young men.
Publisher: Wiley
Date: 07-12-2021
DOI: 10.1113/JP279499
Abstract: Sex differences in exercise physiology, such as substrate metabolism and skeletal muscle fatigability, stem from inherent biological factors, including endogenous hormones and genetics. Studies investigating exercise physiology frequently include only males or do not take sex differences into consideration. Although there is still an underrepresentation of female participants in exercise research, existing studies have identified sex differences in physiological and molecular responses to exercise training. The observed sex differences in exercise physiology are underpinned by the sex chromosome complement, sex hormones and, on a molecular level, the epigenome and transcriptome. Future research in the field should aim to include both sexes, control for menstrual cycle factors, conduct large‐scale and ethnically erse studies, conduct meta‐analyses to consolidate findings from various studies, leverage unique cohorts (such as post‐menopausal, transgender, and those with sex chromosome abnormalities), as well as integrate tissue and cell‐specific ‐omics data. This knowledge is essential for developing deeper insight into sex‐specific physiological responses to exercise training, thus directing future exercise physiology studies and practical application. image
Publisher: Elsevier BV
Date: 11-2019
Publisher: Wiley
Date: 23-07-2013
Publisher: Wiley
Date: 26-08-2021
DOI: 10.1002/RCO2.50
Abstract: Cachexia is a debilitating complication of cancer characterized by progressive wasting and weakness of skeletal muscles that reduces quality of life and can compromise survival. Many anticancer treatments, such as chemotherapy, also cause muscle wasting, which impairs the response to treatment. Given that many cancer patients present with cachexia at the initiation of treatment, we investigated whether cachectic mice were susceptible to chemotherapy‐induced muscle wasting and to investigate contributing mechanisms, including the dysregulation of microRNAs (miRs). Cachectic colon‐26 (C‐26) tumour‐bearing mice were given 5‐fluourouracil (5‐FU) chemotherapy or vehicle treatment and analysed for muscle mass, fibre size and composition, and miR expression. Mechanisms were validated in vitro using C2C12 cell culture and miR mimics and inhibitors and were confirmed in vivo by injecting muscles of 5‐FU‐treated cachectic mice with recombinant adeno‐associated viral (rAAV) vectors encoding a miR sponge. In cachectic tumour‐bearing mice, 5‐FU chemotherapy exacerbated the loss of skeletal muscle mass compared with vehicle treatment (by −12% to −20%, P 0.05). miR expression profiling, quantitative real‐time PCR, and in vitro analyses revealed contributing mechanisms including miR‐351‐3p‐dependent ERK2 inhibition. Intramuscular injection of rAAV vectors encoding a sponge to reduce miR‐351‐3p expression in 5‐FU‐treated cachectic mice enhanced ERK phosphorylation (+18%, P 0.05) and increased muscle fibre size (+15%, P 0.01). Hsa‐miR‐125a‐3p shares similar predicted gene targets as mmu‐miR‐351‐3p, and its inhibition in human muscle cells in vitro prevented 5‐FU‐induced atrophy ( P 0.001) and increased ERK phosphorylation ( P 0.001). The findings implicate miR‐351‐3p‐mediated ERK2 inhibition as a contributing mechanism in chemotherapy‐induced muscle wasting in mice with cancer cachexia and that its inhibition is a promising adjunct therapy for preserving muscles during cancer treatment.
Publisher: Cold Spring Harbor Laboratory
Date: 24-06-2023
DOI: 10.1101/2023.06.22.545905
Abstract: The inter-session reliability of a wide range of measures used to characterize the aging neuromuscular system is unknown, particularly in females. The aim of this study was to determine the inter-session reliability of quadriceps neuromuscular function assessed via maximal voluntary and evoked force and electromyography responses in healthy young and older females. Twenty-six females aged 19 – 74 years completed two identical testing sessions 9 ± 7 days apart. Quadriceps neuromuscular function measurements included isometric maximal voluntary force (MVC), high and low frequency twitch force, voluntary and evoked electromyography (EMG) in superficial quadriceps (RMS, M-wave and H-reflex), and maximal torque (T0), velocity (V0) and power (P MAX ) derived from torque-velocity and power-velocity relationships. Intra-class correlation coefficients (ICC), coefficients of variation (CoV) and Bland-Altman plots were used to assess inter-session reliability. The effect of participant age on inter-session reliability was assessed by linear regression. Excellent reliability (ICC 0.8) was shown for all voluntary and evoked mechanical outcomes and systematic bias was essentially absent. Similarly, all vastus lateralis EMG outcomes showed excellent reliability (ICC 0.8) with CoVs 12%, which were better than vastus medialis and rectus femoris outcomes. Participant age was not associated with inter-session reliability (P 0.05). Excellent reliability of voluntary and evoked force and vastus lateralis EMG outcomes measured in healthy females can be attained in one testing session, irrespective of age, increasing feasibility for future research. The random error should however be considered when quantifying age-related differences and/or adaptation to exercise in female neuromuscular function. The test-retest reliability of a erse range of measures used to quantify neuromuscular function were assessed in younger and older females for the first time. We show that reliable measures of maximal voluntary and evoked quadriceps force and electromyography outcomes can be obtained in one testing session, irrespective of participant age. Thus, neuromuscular function can be accurately assessed across the female lifespan with minimal inconvenience imposed on participants, increasing feasibility for future research.
Publisher: Wiley
Date: 2021
DOI: 10.14814/PHY2.14660
Publisher: Wiley
Date: 08-2020
DOI: 10.14814/PHY2.14520
Publisher: Springer Science and Business Media LLC
Date: 04-2012
DOI: 10.1038/NATURE10980
Abstract: Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder caused by mutations in the dystrophin gene that result in the absence of the membrane-stabilizing protein dystrophin. Dystrophin-deficient muscle fibres are fragile and susceptible to an influx of Ca(2+), which activates inflammatory and muscle degenerative pathways. At present there is no cure for DMD, and existing therapies are ineffective. Here we show that increasing the expression of intramuscular heat shock protein 72 (Hsp72) preserves muscle strength and ameliorates the dystrophic pathology in two mouse models of muscular dystrophy. Treatment with BGP-15 (a pharmacological inducer of Hsp72 currently in clinical trials for diabetes) improved muscle architecture, strength and contractile function in severely affected diaphragm muscles in mdx dystrophic mice. In dko mice, a phenocopy of DMD that results in severe spinal curvature (kyphosis), muscle weakness and premature death, BGP-15 decreased kyphosis, improved the dystrophic pathophysiology in limb and diaphragm muscles and extended lifespan. We found that the sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA, the main protein responsible for the removal of intracellular Ca(2+)) is dysfunctional in severely affected muscles of mdx and dko mice, and that Hsp72 interacts with SERCA to preserve its function under conditions of stress, ultimately contributing to the decreased muscle degeneration seen with Hsp72 upregulation. Treatment with BGP-15 similarly increased SERCA activity in dystrophic skeletal muscles. Our results provide evidence that increasing the expression of Hsp72 in muscle (through the administration of BGP-15) has significant therapeutic potential for DMD and related conditions, either as a self-contained therapy or as an adjuvant with other potential treatments, including gene, cell and pharmacological therapies.
Publisher: Elsevier BV
Date: 2021
DOI: 10.1016/J.JOCD.2019.11.001
Abstract: Inter-/intramuscular fat can be assessed with peripheral Quantitative Computed Tomography (pQCT) and is of interest as an indicator of "muscle quality." Typical pQCT scan sites (forearm, lower leg) have a low amount of inter-/intramuscular fat, however distal diaphyseal femur scan sites with conspicuous inter-/intramuscular fat have been identified as potentially more prudent scan sites, even in healthy adolescents. However, current state of the art analysis methods require labor-intensive manual segmentation of the scan. The purpose of the present study was to evaluate the reliability of a novel open source automated enclosing convex polygon approach (source code jrantal QCT, commit cec9bce) to quantify inter-/intramuscular fat from femoral pQCT scans in healthy adults. The distal diaphyseal femur (25% of tibial length from the knee joint towards the hip) of 27 adults aged 18-50 yr were scanned twice, 1 wk apart, using pQCT. Subcutaneous fat, muscle, inter-/intramuscular fat, and marrow areas, and corresponding densities were evaluated using a method we have reported previously, as well as the novel enclosing convex polygon method. The session-to-session reliability of the assessments was fair to excellent using the previously reported method as indicated by intraclass correlation coefficient (ICC Distal diaphyseal femur appears to be a potentially informative and prudent scan site for inter-/intramuscular fat evaluation with pQCT.
Publisher: American Physiological Society
Date: 08-2020
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.CMET.2015.04.001
Abstract: Accumulation of diacylglycerol (DG) in muscle is thought to cause insulin resistance. DG is a precursor for phospholipids, thus phospholipid synthesis could be involved in regulating muscle DG. Little is known about the interaction between phospholipid and DG in muscle therefore, we examined whether disrupting muscle phospholipid synthesis, specifically phosphatidylethanolamine (PtdEtn), would influence muscle DG content and insulin sensitivity. Muscle PtdEtn synthesis was disrupted by deleting CTP:phosphoethanolamine cytidylyltransferase (ECT), the rate-limiting enzyme in the CDP-ethanolamine pathway, a major route for PtdEtn production. While PtdEtn was reduced in muscle-specific ECT knockout mice, intramyocellular and membrane-associated DG was markedly increased. Importantly, however, this was not associated with insulin resistance. Unexpectedly, mitochondrial biogenesis and muscle oxidative capacity were increased in muscle-specific ECT knockout mice and were accompanied by enhanced exercise performance. These findings highlight the importance of the CDP-ethanolamine pathway in regulating muscle DG content and challenge the DG-induced insulin resistance hypothesis.
Publisher: Frontiers Media SA
Date: 08-07-2016
Publisher: Frontiers Media SA
Date: 26-08-2014
Publisher: Public Library of Science (PLoS)
Date: 02-12-2014
Publisher: American Physiological Society
Date: 08-2019
DOI: 10.1152/JAPPLPHYSIOL.00904.2018
Abstract: Noncoding RNAs, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) play roles in the development and homeostasis of nearly every tissue of the body, including the regulation of processes underlying heart growth. Cardiac hypertrophy can be classified as either physiological (beneficial heart growth) or pathological (detrimental heart growth), the latter of which results in impaired cardiac function and heart failure and is predictive of a higher incidence of death due to cardiovascular disease. Several miRNAs have a functional role in exercise-induced cardiac hypertrophy, while both miRNAs and lncRNAs are heavily involved in pathological heart growth and heart failure. The latter have the potential to act as an endogenous sponge RNA and interact with specific miRNAs to control cardiac hypertrophy, adding another level of complexity to our understanding of the regulation of cardiac muscle mass. In addition to tissue-specific effects, ncRNA-mediated tissue cross talk occurs via exosomes. In particular, miRNAs can be internalized in exosomes and secreted from various cardiac and vascular cell types to promote angiogenesis, as well as protection and repair of ischemic tissues. ncRNAs hold promising therapeutic potential to protect the heart against ischemic injury and aid in regeneration. Numerous preclinical studies have demonstrated the therapeutic potential of ncRNAs, specifically miRNAs, for the treatment of cardiovascular disease. Most of these studies employ antisense oligonucleotides to inhibit miRNAs of interest however, off-target effects often limit their potential to be translated to the clinic. In this context, approaches using viral and nonviral delivery tools are promising means to provide targeted delivery in vivo.
Publisher: American Physiological Society
Date: 09-2017
DOI: 10.1152/AJPENDO.00043.2017
Abstract: Impairments in mitochondrial function and substrate metabolism are implicated in the etiology of obesity and Type 2 diabetes. MicroRNAs (miRNAs) can degrade mRNA or repress protein translation and have been implicated in the development of such disorders. We used a contrasting rat model system of selectively bred high- (HCR) or low- (LCR) intrinsic running capacity with established differences in metabolic health to investigate the molecular mechanisms through which miRNAs regulate target proteins mediating mitochondrial function and substrate oxidation processes. Quantification of select miRNAs using the rat miFinder miRNA PCR array revealed differential expression of 15 skeletal muscles (musculus tibialis anterior) miRNAs between HCR and LCR rats (14 with higher expression in LCR P 0.05). Ingenuity Pathway Analysis predicted these altered miRNAs to collectively target multiple proteins implicated in mitochondrial dysfunction and energy substrate metabolism. Total protein abundance of citrate synthase (CS miR-19 target) and voltage-dependent anion channel 1 (miR-7a target) were higher in HCR compared with LCR cohorts (~57 and ~26%, respectively P 0.05). A negative correlation was observed for miR-19a-3p and CS ( r = 0.32, P = 0.015) protein expression. To determine whether miR-19a-3p can regulate CS in vitro, we performed luciferase reporter and transfection assays in C2C12 myotubes. MiR-19a-3p binding to the CS untranslated region did not change luciferase reporter activity however, miR-19a-3p transfection decreased CS protein expression (∼70% P 0.05). The differential miRNA expression targeting proteins implicated in mitochondrial dysfunction and energy substrate metabolism may contribute to the molecular basis, mediating the ergent metabolic health profiles of LCR and HCR rats.
Publisher: Wiley
Date: 31-07-2018
DOI: 10.1113/EP086846
Publisher: Wiley
Date: 27-10-2006
Publisher: Wiley
Date: 17-01-2014
DOI: 10.1113/EXPPHYSIOL.2013.077255
Abstract: New Findings What is the central question of this study? The Notch signalling pathway plays an important role in muscle regeneration, and activation of the pathway has been shown to enhance muscle regeneration in aged mice. It is unknown whether Notch activation will have a similarly beneficial effect on muscle regeneration in the context of Duchenne muscular dystrophy (DMD). What is the main finding and its importance? Although expression of Notch signalling components is altered in both mouse models of DMD and in human DMD patients, activation of the Notch signalling pathway does not confer any functional benefit on muscles from dystrophic mice, suggesting that other signalling pathways may be more fruitful targets for manipulation in treating DMD. Abstract In Duchenne muscular dystrophy (DMD), muscle damage and impaired regeneration lead to progressive muscle wasting, weakness and premature death. The Notch signalling pathway represents a central regulator of gene expression and is critical for cellular proliferation, differentiation and apoptotic signalling during all stages of embryonic muscle development. Notch activation improves muscle regeneration in aged mice, but its potential to restore regeneration and function in muscular dystrophy is unknown. We performed a comprehensive examination of several genes involved in Notch signalling in muscles from dystrophin-deficient mdx and dko (utrophin- and dystrophin-null) mice and DMD patients. A reduction of Notch1 and Hes1 mRNA in tibialis anterior muscles of dko mice and quadriceps muscles of DMD patients and a reduction of Hes1 mRNA in the diaphragm of the mdx mice were observed, with other targets being inconsistent across species. Activation and inhibition of Notch signalling, followed by measures of muscle regeneration and function, were performed in the mouse models of DMD. Notch activation had no effect on functional regeneration in C57BL/10, mdx or dko mice. Notch inhibition significantly depressed the frequency-force relationship in regenerating muscles of C57BL/10 and mdx mice after injury, indicating reduced force at each stimulation frequency, but enhanced the frequency-force relationship in muscles from dko mice. We conclude that while Notch inhibition produces slight functional defects in dystrophic muscle, Notch activation does not significantly improve muscle regeneration in murine models of muscular dystrophy. Furthermore, the inconsistent expression of Notch targets between murine models and DMD patients suggests caution when making interspecies comparisons.
Publisher: Springer Science and Business Media LLC
Date: 12-06-2019
DOI: 10.1007/S40279-019-01132-7
Abstract: Resistance training is essential for health and performance and confers many benefits such as increasing skeletal muscle mass, increasing strength and power output, and improving metabolic health. Resistance training is a major component of the physical activity guidelines, yet research in female populations is limited. Recent increases in the promotion of, and the participation by, females in sport and exercise, highlight the need for an increase in understanding of evidence-based best practice exercise prescription for females. The aim of this review is to provide an overview of the current research regarding resistance training performance and skeletal muscle adaptation in females, with a focus on the hormonal variables that may influence resistance training outcomes. Findings suggest that the menstrual cycle phase may impact strength, but not skeletal muscle protein metabolism. In comparison, oral contraception use in females may reduce skeletal muscle protein synthesis, but not strength outcomes, when compared to non-users. Future research should investigate the role of resistance training in the maintenance of skeletal muscle protein metabolism during pregnancy, menopause and in athletes experiencing relative energy deficiency in sport. The review concludes with recommendations for researchers to assist them in the inclusion of female participants in resistance training research specifically, with commentary on the most appropriate methods of controlling for, or understanding the implications of, hormonal fluctuations. For practitioners, the current evidence suggests possible resistance training practices that could optimise performance outcomes in females, although further research is warranted.
Publisher: Cold Spring Harbor Laboratory
Date: 06-08-2020
DOI: 10.1101/2020.08.04.20168542
Abstract: Testosterone is a naturally occurring hormone that has been positively associated with lean mass and strength in males. Whether endogenous testosterone is related to lean mass and strength in females is unknown. To examine the relationship between endogenous testosterone concentration and lean mass and handgrip strength in healthy, pre-menopausal females. Secondary data from the 2013-2014 National Health and Nutrition Examination Survey (NHANES)were used. Females were aged 18-40 (n=753, age 30 ± 6 yr, mean ± SD) and pre-menopausal. Multivariate linear regression models were used to examine associations between total testosterone, height-adjusted lean mass and handgrip strength. Mean ± SD testosterone concentration was 1.0 ± 0.6 nmol·L -1 and mean free androgen index (FAI) was 0.02 ± 0.02. Mean fat-free mass index (FFMI) was 16.4 ± 3.0 kg·m -2 and mean handgrip strength was 61.7 ± 10.5 kg. In females, testosterone was not associated with FFMI (β=0.08 95%CI: −0.02, 0.18 p=0.11) or handgrip strength (β=0.03 95%CI: −0.11, 0.17 p=0.67) in a statistically significant manner. Conversely, FAI was positively associated with FFMI (β=0.17 95%CI: 0.01, 0.33 p=0.04 ) but not handgrip strength (β=0.19 95%CI: −0.02, 0.21 p=0.10 ). These findings indicate that FAI, but not total testosterone, is associated with FFMI in females. The small coefficients however suggest that FAI only accounts for a minor proportion of the variance in FFMI, highlighting the complexity of the regulation of lean mass in female physiology. FAI nor total testosterone are associated with handgrip strength in females when testosterone concentrations are not altered pharmacologically.
Publisher: American Physiological Society
Date: 10-2023
Publisher: Frontiers Media SA
Date: 10-2018
Publisher: Frontiers Media SA
Date: 26-11-2014
Publisher: Springer Science and Business Media LLC
Date: 11-12-2015
DOI: 10.1038/SREP17535
Abstract: Follistatin is an inhibitor of TGF-β superfamily ligands that repress skeletal muscle growth and promote muscle wasting. Accordingly, follistatin has emerged as a potential therapeutic to ameliorate the deleterious effects of muscle atrophy. However, it remains unclear whether the anabolic effects of follistatin are conserved across different modes of non-degenerative muscle wasting. In this study, the delivery of a recombinant adeno-associated viral vector expressing follistatin (rAAV:Fst) to the hind-limb musculature of mice two weeks prior to denervation or tenotomy promoted muscle hypertrophy that was sufficient to preserve muscle mass comparable to that of untreated sham-operated muscles. However, administration of rAAV:Fst to muscles at the time of denervation or tenotomy did not prevent subsequent muscle wasting. Administration of rAAV:Fst to innervated or denervated muscles increased protein synthesis, but markedly reduced protein degradation only in innervated muscles. Phosphorylation of the signalling proteins mTOR and S6RP, which are associated with protein synthesis, was increased in innervated muscles administered rAAV:Fst, but not in treated denervated muscles. These results demonstrate that the anabolic effects of follistatin are influenced by the interaction between muscle fibres and motor nerves. These findings have important implications for understanding the potential efficacy of follistatin-based therapies for non-degenerative muscle wasting.
Publisher: Cold Spring Harbor Laboratory
Date: 24-07-2023
DOI: 10.1101/2023.07.22.550175
Abstract: Cardiomyocyte calcium homeostasis is a tightly regulated process. The mitochondrial calcium uniporter (MCU) complex can buffer elevated cytosolic Ca 2+ levels and consists of pore-forming proteins including MCU, and various regulatory proteins such as mitochondrial calcium uptake proteins 1 and 2 (MICU1/2). The stoichiometry of these proteins influences the sensitivity to Ca 2+ and activity of the complex. However, the factors that regulate their gene expression remain incompletely understood. Long non-coding RNAs (lncRNAs) regulate gene expression through various mechanisms, and we recently found that the lncRNA Tug1 increased the expression of Mcu and associated genes. To further explore this, we performed antisense LNA knockdown of Tug1 ( Tug1 KD) in H9c2 rat cardiomyocytes. Tug1 KD increased MCU protein expression, yet pyruvate dehydrogenase dephosphorylation, which is indicative of mitochondrial Ca 2+ uptake was not enhanced. However, RNA-seq revealed that Tug1 KD increased Mcu along with differential expression of genes including many related to Ca 2+ regulation pathways in the heart. To understand the effect of this on Ca 2+ signalling, we measured phosphorylation of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) and its downstream target cAMP Response Element-Binding protein (CREB), a transcription factor known to drive Mcu gene expression. In response a Ca 2+ stimulus, the increase in CaMKII and CREB phosphorylation was attenuated by Tug1 KD. Inhibition of CaMKII, but not CREB, partially prevented the Tug1 KD- mediated increase in Mcu . Together, these data suggest that Tug1 modulates MCU expression via a mechanism involving CaMKII and regulates cardiomyocyte Ca 2+ signalling which could have important implications for cardiac function.
Publisher: Frontiers Media SA
Date: 24-02-2015
Publisher: Informa UK Limited
Date: 13-04-2019
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.BBALIP.2014.12.002
Abstract: Hepatic insulin resistance is a major risk factor for the development of type 2 diabetes and is associated with the accumulation of lipids, including diacylglycerol (DAG), triacylglycerols (TAG) and ceramide. There is evidence that enzymes involved in ceramide or sphingolipid metabolism may have a role in regulating concentrations of glycerolipids such as DAG and TAG. Here we have investigated the role of sphingosine kinase (SphK) in regulating hepatic lipid levels. We show that mice on a high-fat high-sucrose diet (HFHS) displayed glucose intolerance, elevated liver TAG and DAG, and a reduction in total hepatic SphK activity. Reduced SphK activity correlated with downregulation of SphK1, but not SphK2 expression, and was not associated with altered ceramide levels. The role of SphK1 was further investigated by overexpressing this isoform in the liver of mice in vivo. On a low-fat diet (LFD) mice overexpressing liver SphK1, displayed reduced hepatic TAG synthesis and total TAG levels, but with no change to DAG or ceramide. These mice also exhibited no change in gluconeogenesis, glycogenolysis or glucose tolerance. Similarly, overexpression of SphK1 had no effect on the pattern of endogenous glucose production determined during a glucose tolerance test. Under HFHS conditions, normalization of liver SphK activity to levels observed in LFD controls did not alter hepatic TAG concentrations. Furthermore, DAG, ceramide and glucose tolerance were also unaffected. In conclusion, our data suggest that SphK1 plays an important role in regulating TAG metabolism under LFD conditions.
Publisher: Cold Spring Harbor Laboratory
Date: 21-12-2022
DOI: 10.1101/2022.12.20.22283756
Abstract: Cell-free microRNAs (cf-miRNAs) are secreted from cells and transported via the blood to exert their effect on target tissues. Numerous pathophysiological adaptations, including exercise, alter cf-miRNA levels. The aim of the systematic review was to investigate the cf-miRNA response to an acute bout of exercise and to interpret it using a robust correlated and hierarchical effects (CHE) meta-analysis. The systematic review was registered in PROSPERO (CRD42021256303). A CHE meta-analysis was used to compare the changes in cf-miRNA levels and the influence of exercise modality. An exploratory machine-learning-based approach was used to capture influential moderators. Primary studies were retrieved from PubMed and SPORTDiscus (09.03.2022). Relative changes in cf-miRNA expression in response to exercise were computed for each study. The ROBINS-I, GRADE and AMSTAR2 tools were used to assess evidence certainty and risk of bias. Thirty-six studies including an acute exercise intervention in N=880 healthy males and females aged 18-45yrs met the eligibility criteria. Muscle enriched cf-miR-1 (N=320), cf-miR-133a (N=195) and cf-miR-133b (N=132) levels increased 1-2hr (cf-miR1: FC = 2.72, 95% CI= 1.5-4.0 cf-miR133a: FC = 2.10, 95% CI = 1.6-2.6 cf-miR-133b: FC = 2.39, 95% CI = 1.2-3.6) and 24 hr post-exercise (cf-miR1: FC = 2.25, 95% CI= 1.3-3.2 cf-miR133a: FC = 1.81, 95% CI = 1.4-2.2 cf-miR-133b: FC = 1.99, 95% CI = 1.2-2.8). Acute exercise triggers temporal and modality specific responses in cf-miRNAs. levels. Influential moderators included s le size, collection time point, exercise modality, age and the use of various technical quality controls. Exercise acutely alters cell-free miRNA (cf-miRNA) levels in human serum and plasma, but research is poorly reproducible Muscle-enriched cf-miRNA levels robustly increase following an acute bout of exercise, with temporal and modality specific responses The implementation of a CHE model, a novel statistical approach within the miRNA field, allowed to identify key methodological factors moderating cf-miRNA levels. Strict implementation of these factors is warranted to improve rigour and reproducibility in this field.
Publisher: Wiley
Date: 14-04-2009
Publisher: Cold Spring Harbor Laboratory
Date: 23-05-2023
DOI: 10.1101/2023.05.18.23290199
Abstract: Ageing is associated with a loss of skeletal muscle mass and function that negatively impacts the independence and quality of life of older in iduals. Females demonstrate a distinct pattern of muscle ageing compared to males, potentially due to menopause where endogenous sex hormone production declines. This systematic review aims to investigate the current knowledge about the role of oestrogen in female skeletal muscle ageing. A systematic search of MEDLINE complete, Global Health, Embase, PubMed, SPORTDiscus, and CINHAL was conducted. Studies were considered eligible if they compared a state of oestrogen deficiency (e.g. postmenopausal females) or supplementation (e.g. oestrogen replacement therapy) to normal oestrogen conditions (e.g. premenopausal females or no supplementation). Outcome variables of interest included measures of skeletal muscle mass, function, damage/repair, and energy metabolism. Quality assessment was completed with the relevant Johanna Briggs critical appraisal tool, and data were synthesised in a narrative manner. Thirty-two studies were included in the review. Compared to premenopausal females, postmenopausal females display reduced muscle mass and strength, but the effect of menopause on markers of muscle damage and expression of the genes involved in metabolic signalling pathways remains unclear. Some studies suggest a beneficial effect of oestrogen replacement therapy on muscle size and strength, but evidence is largely conflicting and inconclusive, potentially due to large variations in the reporting and status of exposure and outcomes. The findings from this review points toward a potential negative effect of oestrogen deficiency in ageing skeletal muscle, but further mechanistic evidence is needed to clarify its role. The role of oestrogen in female skeletal muscle ageing. ↑ = significant increase, ↓ = significant decrease, ≠ = significantly different, ? = mixed evidence, p .05. ALM: appendicular lean mass AMPK: adenosine monophosphate kinase CSA: cross-sectional area PGC-1α: peroxisome proliferator-activated receptor gamma coactivator 1-alpha. Created with BioRender.com .
Publisher: F1000 Research Ltd
Date: 31-08-2018
DOI: 10.12688/F1000RESEARCH.15258.1
Abstract: The forkhead box O3 (FOXO3, or FKHRL1) protein is a member of the FOXO subclass of transcription factors. FOXO proteins were originally identified as regulators of insulin-related genes however, they are now established regulators of genes involved in vital biological processes, including substrate metabolism, protein turnover, cell survival, and cell death. FOXO3 is one of the rare genes that have been consistently linked to longevity in in vivo models. This review provides an update of the most recent research pertaining to the role of FOXO3 in (i) the regulation of protein turnover in skeletal muscle, the largest protein pool of the body, and (ii) the genetic basis of longevity. Finally, it examines (iii) the role of microRNAs in the regulation of FOXO3 and its impact on the regulation of the cell cycle.
Publisher: American Chemical Society (ACS)
Date: 21-04-2021
Publisher: Wiley
Date: 27-05-2021
DOI: 10.1113/EP089253
Abstract: What is the central question of this study? Striated muscle activator of rho signalling (STARS) is an actin‐binding protein that regulates transcriptional pathways controlling muscle function, growth and myogenesis, processes that are impaired in dystrophic muscle: what is the regulation of the STARS pathway in Duchenne muscular dystrophy (DMD)? What is the main finding and its importance? Members of the STARS signalling pathway are reduced in the quadriceps of patients with DMD and in mouse models of muscular dystrophy. Overexpression of STARS in the dystrophic deficient mdx mouse model increased maximal isometric specific force and upregulated members of the actin cytoskeleton and oxidative phosphorylation pathways. Regulating STARS may be a therapeutic approach to enhance muscle health. Duchenne muscular dystrophy (DMD) is characterised by impaired cytoskeleton organisation, cytosolic calcium handling, oxidative stress and mitochondrial dysfunction. This results in progressive muscle damage, wasting and weakness and premature death. The striated muscle activator of rho signalling (STARS) is an actin‐binding protein that activates the myocardin‐related transcription factor‐A (MRTFA)/serum response factor (SRF) transcriptional pathway, a pathway regulating cytoskeletal structure and muscle function, growth and repair. We investigated the regulation of the STARS pathway in the quadriceps muscle from patients with DMD and in the tibialis anterior (TA) muscle from the dystrophin‐deficient mdx and dko (utrophin and dystrophin null) mice. Protein levels of STARS, SRF and RHOA were reduced in patients with DMD. STARS , SRF and MRTFA mRNA levels were also decreased in DMD muscle, while Stars mRNA levels were decreased in the mdx mice and Srf and Mrtfa mRNAs decreased in the dko mice. Overexpressing human STARS (hSTARS) in the TA muscles of mdx mice increased maximal isometric specific force by 13% ( P 0.05). This was not associated with changes in muscle mass, fibre cross‐sectional area, fibre type, centralised nuclei or collagen deposition. Proteomics screening followed by pathway enrichment analysis identified that hSTARS overexpression resulted in 31 upregulated and 22 downregulated proteins belonging to the actin cytoskeleton and oxidative phosphorylation pathways. These pathways are impaired in dystrophic muscle and regulate processes that are vital for muscle function. Increasing the STARS protein in dystrophic muscle improves muscle force production, potentially via synergistic regulation of cytoskeletal structure and energy production.
Publisher: Springer Science and Business Media LLC
Date: 13-05-2021
DOI: 10.1038/S41598-021-89232-1
Abstract: The aim of this study was to examine the relationship between endogenous testosterone concentrations and lean mass and handgrip strength in healthy, pre-menopausal females. Testosterone has been positively associated with lean mass and strength in young and older males. Whether this relationship exists in pre-menopausal females is unknown. Secondary data from the 2013–2014 National Health and Nutrition Examination Survey were used to test this relationship. Females were aged 18–40 (n = 716, age 30 ± 6 years, mean ± SD) and pre-menopausal. Multivariate linear regression models were used to examine associations between total testosterone, lean mass index (LMI) and handgrip strength. Mean ± SD testosterone concentration was 1.0 ± 0.6 nmol L −1 and mean free androgen index (FAI) was 0.02 ± 0.02. In pre-menopausal females, testosterone was not associated with LMI (β = 0.05 95%CI − 0.04, 0.15 p = 0.237) or handgrip strength (β = 0.01 95%CI − 0.11, 0.12 p = 0.926) in a statistically significant manner. Conversely, FAI was associated with LMI (β = − 0.03 95%CI − 0.05, − 0.02 p = 0.000) in a quadratic manner, meaning LMI increases with increasing FAI levels. Handgrip strength was not associated with FAI (β = 0.06 95%CI − 0.02, 0.15 p = 0.137) . These findings indicate that FAI, but not total testosterone, is associated with LMI in pre-menopausal females. Neither FAI nor total testosterone are associated with handgrip strength in pre-menopausal females when testosterone concentrations are not altered pharmacologically.
No related organisations have been discovered for Severine Lamon.
Start Date: 2020
End Date: 2022
Funder: Australian Research Council
View Funded ActivityStart Date: 2015
End Date: 12-2017
Amount: $342,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2022
End Date: 12-2025
Amount: $941,120.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2020
End Date: 12-2024
Amount: $444,000.00
Funder: Australian Research Council
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