Exercise-induced gene expression changes in skeletal muscle of old mice (original) (raw)
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Mechanisms of Ageing and Development, 2000
The gene expression profile of skeletal muscle from healthy older (62 -75 years old) compared with younger (20-34 years old) men demonstrated elevated expression of genes typical of a stress or damage response, and decreased expression of a gene encoding a DNA repair/cell cycle checkpoint protein. Although the expression of these genes was relatively unaffected by a single bout of resistance exercise in older men, acute exercise altered gene expression in younger men such that post-exercise gene expression in younger men was similar to baseline gene expression in older men. The lack of response of muscle from older subjects to resistance exercise was also apparent in the expression of the inflammatory response gene IL-1b, which did not differ between the age groups at baseline, but increased within 24 h of the exercise bout only in younger subjects. Other genes with potentially important roles in the adaptation of muscle to exercise, specifically in the processes of angiogenesis and cell proliferation, showed a similar response to exercise in older compared with younger subjects. Only one gene encoding the multifunctional, early growth response transcription factor EGR-1, showed an opposite pattern of expression in response to exercise, acutely decreasing in younger and increasing in older subjects. These results may provide a molecular basis for the inherent variability in the response of muscle from older as www.elsevier.com/locate/mechagedev : S 0 0 4 7 -6 3 7 4 ( 0 0 ) 0 0 1 7 8 -0 A.C. Jozsi et al. / Mechanisms of Ageing and De6elopment 120 (2000) 45-56 46 compared with younger individuals to resistance training.
Skeletal Muscle Gene Expression in Long-Term Endurance and Resistance Trained Elderly
International Journal of Molecular Sciences
Physical exercise is deemed the most efficient way of counteracting the age-related decline of skeletal muscle. Here we report a transcriptional study by next-generation sequencing of vastus lateralis biopsies from elderly with a life-long high-level training practice (n = 9) and from age-matched sedentary subjects (n = 5). Unsupervised mixture distribution analysis was able to correctly categorize trained and untrained subjects, whereas it failed to discriminate between individuals who underwent a prevalent endurance (n = 5) or a prevalent resistance (n = 4) training, thus showing that the training mode was not relevant for sarcopenia prevention. KEGG analysis of transcripts showed that physical exercise affected a high number of metabolic and signaling pathways, in particular those related to energy handling and mitochondrial biogenesis, where AMPK and AKT-mTOR signaling pathways are both active and balance each other, concurring to the establishment of an insulin-sensitive phenot...
Skeletal muscle transcriptome in healthy aging
Nature Communications
Age-associated changes in gene expression in skeletal muscle of healthy individuals reflect accumulation of damage and compensatory adaptations to preserve tissue integrity. To characterize these changes, RNA was extracted and sequenced from muscle biopsies collected from 53 healthy individuals (22–83 years old) of the GESTALT study of the National Institute on Aging–NIH. Expression levels of 57,205 protein-coding and non-coding RNAs were studied as a function of aging by linear and negative binomial regression models. From both models, 1134 RNAs changed significantly with age. The most differentially abundant mRNAs encoded proteins implicated in several age-related processes, including cellular senescence, insulin signaling, and myogenesis. Specific mRNA isoforms that changed significantly with age in skeletal muscle were enriched for proteins involved in oxidative phosphorylation and adipogenesis. Our study establishes a detailed framework of the global transcriptome and mRNA isof...
Skeletal muscle in aged mice reveals extensive transformation of muscle gene expression
BMC Genetics
Background: Aging leads to decreased skeletal muscle function in mammals and is associated with a progressive loss of muscle mass, quality and strength. Age-related muscle loss (sarcopenia) is an important health problem associated with the aged population. Results: We investigated the alteration of genome-wide transcription in mouse skeletal muscle tissue (rectus femoris muscle) during aging using a high-throughput sequencing technique. Analysis revealed significant transcriptional changes between skeletal muscles of mice at 3 (young group) and 24 (old group) months of age. Specifically, genes associated with energy metabolism, cell proliferation, muscle myosin isoforms, as well as immune functions were found to be altered. We observed several interesting gene expression changes in the elderly, many of which have not been reported before. Conclusions: Those data expand our understanding of the various compensatory mechanisms that can occur with age, and further will assist in the development of methods to prevent and attenuate adverse outcomes of aging.
Molecular Networks of Human Muscle Adaptation to Exercise and Age
2013
Physical activity and molecular ageing presumably interact to precipitate musculoskeletal decline in humans with age. Herein, we have delineated molecular networks for these two major components of sarcopenic risk using multiple independent clinical cohorts. We generated genome-wide transcript profiles from individuals (n = 44) who then undertook 20 weeks of supervised resistance-exercise training (RET). Expectedly, our subjects exhibited a marked range of hypertrophic responses (3% to +28%), and when applying Ingenuity Pathway Analysis (IPA) up-stream analysis to ,580 genes that covaried with gain in lean mass, we identified rapamycin (mTOR) signaling associating with growth (P = 1.4610 230 ). Paradoxically, those displaying most hypertrophy exhibited an inhibited mTOR activation signature, including the striking down-regulation of 70 rRNAs. Differential analysis found networks mimicking developmental processes (activated all-transretinoic acid (ATRA, Z-score = 4.5; P = 6610 213 ) and inhibited aryl-hydrocarbon receptor signaling (AhR, Z-score = 22.3; P = 3610 27 )) with RET. Intriguingly, as ATRA and AhR gene-sets were also a feature of endurance exercise training (EET), they appear to represent ''generic'' physical activity responsive gene-networks. For age, we found that differential geneexpression methods do not produce consistent molecular differences between young versus old individuals. Instead, utilizing two independent cohorts (n = 45 and n = 52), with a continuum of subject ages (18-78 y), the first reproducible set of age-related transcripts in human muscle was identified. This analysis identified ,500 genes highly enriched in posttranscriptional processes (P = 1610 26 ) and with negligible links to the aforementioned generic exercise regulated gene-sets and some overlap with ribosomal genes. The RNA signatures from multiple compounds all targeting serotonin, DNA topoisomerase antagonism, and RXR activation were significantly related to the muscle age-related genes. Finally, a number of specific chromosomal loci, including 1q12 and 13q21, contributed by more than chance to the age-related gene list (P = 0.01-0.005), implying possible epigenetic events. We conclude that human muscle age-related molecular processes appear distinct from the processes regulated by those of physical activity.
Journal of Strength and Conditioning Research, 2013
Sunderland, KL, Roberts, MD, Dalbo, VJ, and Kerksick, CM. Aging and sequential resistance exercise bout effects on housekeeping gene messenger RNA expression in human skeletal muscle. J Strength Cond Res 27(1): 1-7, 2013-The purpose of this study was to investigate how age and 1 week of conventional resistance exercise affects commonly used housekeeping gene (HKG) messenger RNAs (mRNAs) in skeletal muscle. Ten college-aged (18-25 years) and 10 older (60-76 years) men completed 3 lower-body resistance exercise bouts on Monday, Wednesday, and Friday, and muscle samples were obtained before bout 1 (T1), 48 hours after the first (T2) and second bouts (T3), and 24 hours after the third bout (T4). Raw Ct values indicated that b-actin and cyclophilin were more highly expressed in older vs. younger males (p , 0.01) at T1. When normalizing each HKG mRNA to the other 4 HKG mRNAs, CYC increased at T3 and glyceraldehyde-3phosphate dehydrogenase decreased at T2 (p , 0.05) in younger men. This is one of the few studies to suggest that explicit HKG mRNAs should be used depending upon age group and resistance exercise intervention.
Sport Sciences for Health, 2012
Ageing in humans is associated with physiological loss of strength and skeletal muscle fibres, known as sarcopenia. This results in loss of mobility and independence in the elderly, and is a major socioeconomic and public health issue. Progression of sarcopenia can be influenced by a range of concomitant factors. In our ongoing investigations into the effects on skeletal muscle of specific and intensity-graduated endurance and resistance training, we investigated the associated muscle adaptation at the molecular level through transcription profile analysis. Although the 12-week training programmes appeared to have little benefit, with increases in muscle strength of 1-2%, the transcriptional profiles obtained from tiny percutaneous needle biopsies of the vastus lateralis muscle demonstrated that the training was specific and efficient. This classification of the transcriptome in terms of the functional groupings of the gene expression profiles associated with the endurance and resistance training programmes provides a signature of the muscle responsiveness to the specific training. Therefore, such analyses could provide a useful tool to personalize specific skeletal muscle training, and they indicate that both endurance and resistance training should indeed be incorporated into weekly scheduled exercise in elderly subjects.
Experimental Gerontology, 2010
A compromised muscle function due to aging, sarcopenia and reduced level of physical activity can lead to metabolic complications and chronic diseases. Endurance exercise counters these diseases by inducing beneficial adaptations whose molecular mechanisms remain unclear. We have investigated the transcriptomic changes following mild-intensity endurance training in skeletal muscle of elderly men. Seven healthy subjects followed an exercise program of cycle ergometer training at lactate threshold (LT) level for 60 min/ day, five times/week during six weeks. Physiological and transcriptomic changes were analyzed before and after training. LT training decreased percentage body fat and fasting levels of plasma glucose, while increasing high-density lipoprotein cholesterol and lecithin-cholesterol acyltransferase levels. Transcriptomic analysis revealed fast-to-slow fiber type transition, increased amount of mtDNA encoded transcripts and modulation of 12 transcripts notably related to extracellular matrix (ECM), oxidative phosphorylation (OXPHOS), as well as partially characterized and novel transcripts. The training simultaneously induced the expression of genes related to slow fiber type transition, OXPHOS and ECM, which might contribute to the improvement of glucose and lipid metabolisms and whole body aerobic capacity.
International Journal of Molecular Sciences
In a previous study, the whole transcriptome of the vastus lateralis muscle from sedentary elderly and from age-matched athletes with an exceptional record of high-intensity, life-long exercise training was compared—the two groups representing the two extremes on a physical activity scale. Exercise training enabled the skeletal muscle to counteract age-related sarcopenia by inducing a wide range of adaptations, sustained by the expression of protein-coding genes involved in energy handling, proteostasis, cytoskeletal organization, inflammation control, and cellular senescence. Building on the previous study, we examined here the network of non-coding RNAs participating in the orchestration of gene expression and identified differentially expressed micro- and long-non-coding RNAs and some of their possible targets and roles. Unsupervised hierarchical clustering analyses of all non-coding RNAs were able to discriminate between sedentary and trained individuals, regardless of the exerc...
Resistance exercise reverses aging in human skeletal muscle
2007
Human aging is associated with skeletal muscle atrophy and functional impairment (sarcopenia). Multiple lines of evidence suggest that mitochondrial dysfunction is a major contributor to sarcopenia. We evaluated whether healthy aging was associated with a transcriptional profile reflecting mitochondrial impairment and whether resistance exercise could reverse this signature to that approximating a younger physiological age. Skeletal muscle biopsies from healthy older (N = 25) and younger (N = 26) adult men and women were compared using gene expression profiling, and a subset of these were related to measurements of muscle strength. 14 of the older adults had muscle samples taken before and after a six-month resistance exercise-training program. Before exercise training, older adults were 59% weaker than younger, but after six months of training in older adults, strength improved significantly (P,0.001) such that they were only 38% lower than young adults. As a consequence of age, we found 596 genes differentially expressed using a false discovery rate cutoff of 5%. Prior to the exercise training, the transcriptome profile showed a dramatic enrichment of genes associated with mitochondrial function with age. However, following exercise training the transcriptional signature of aging was markedly reversed back to that of younger levels for most genes that were affected by both age and exercise. We conclude that healthy older adults show evidence of mitochondrial impairment and muscle weakness, but that this can be partially reversed at the phenotypic level, and substantially reversed at the transcriptome level, following six months of resistance exercise training.