Age-dependent impact of two exercise training regimens on genomic and metabolic remodeling in skeletal muscle and liver of male mice
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ABSTRACT: How skeletal muscle adapts to different types of exercise intensity with age is not known. Adult and old C57BL/6 male mice were assigned to one of three groups: sedentary, daily high-intensity intermittent training (HIIT), or moderate intensity continuous training (MICT) for 4 weeks, compatible with the older group’s exercise capacity. Improvements in body composition, fasting blood glucose, and muscle strength were mostly observed in the MICT old group, while effects of HIIT training in adult and old animals was less clear. Skeletal muscle exhibited structural and functional adaptations to exercise training, as revealed by electron microscopy, OXPHOS assays, respirometry, and muscle protein biomarkers. Transcriptomics analysis of gastrocnemius muscle combined with liver and serum metabolomics unveiled an age-dependent metabolic remodeling in response to exercise training. These results support a tailored exercise prescription approach aimed at improving health and ameliorating age-associated loss of muscle strength and function in the elderly.
Project description:How skeletal muscle adapts to different types of exercise intensity with age is not known. Young and old C57BL/6 male mice were assigned to either a sedentary or two types of exercise regimes consisting of daily high-intensity intermittent (HIIT) or moderate intensity continuous (MICT) training for 4 weeks, compatible with the older group’s exercise capacity. Body composition, fasting blood glucose levels, and muscle strength were improved in exercised old mice compared to sedentary controls, while the exercise benefits were absent in younger animals. Skeletal muscle exhibited structural and functional adaptations in response to exercise, as revealed by electron microscopy, OXPHOS assays, respirometry, and PGC-1 and LC3-II protein levels. Transcriptomics analysis of gastrocnemius muscle combined with liver and serum metabolomics unveiled an age-dependent metabolic remodeling provoked by exercise through mitochondrial biogenesis, energy metabolism, and cellular plasticity. These results are supportive of a tailored exercise prescription approach with the goal of improving health and ameliorating age-associated loss of muscle mass, strength and function in the elderly.
Project description:The molecular transducers of benefits from different exercise modalities remain incompletely defined. Here we report that 12 weeks of high-intensity aerobic interval (HIIT), resistance (RT), and combined exercise training enhanced insulin sensitivity and lean mass, but only HIIT and combined training improved aerobic capacity and skeletal muscle mitochondrial respiration. HIIT revealed a more robust increase in gene transcripts than other exercise modalities, particularly in older adults, although little overlap with corresponding individual protein abundance was noted. HIIT reversed many age-related differences in the proteome, particularly of mitochondrial proteins in concert with increased mitochondrial protein synthesis. Both RT and HIIT enhanced proteins involved in translational machinery irrespective of age. Only small changes of methylation of DNA promoter regions were observed. We provide evidence for predominant exercise regulation at the translational level, enhancing translational capacity and proteome abundance to explain phenotypic gains in muscle mitochondrial function and hypertrophy in all ages.
Project description:High-intensity intermittent exercise training (HIIT) has been proposed as an effective approach for improving both anaerobic and aerobic capacities. However, the molecular response of muscles to HIIT remains unknown. We used microarray to examine the effects of HIIT on global gene expression in human skeletal muscle.
Project description:Skeletal muscle tissue is a highly adaptable tissue, responding to the specific demands it is subjected to. High-intensity interval training (HIIT) has been shown to generate similar, or even greater, molecular changes in skeletal muscle as that of constant load longer-lasting endurance-type training at moderate intensities. Despite shorter exposure times, the higher intensity provided by HIIT training leads to greater metabolic perturbations and thereby larger improvements in mitochondrial content and maximal oxygen uptake. During a period of regular exercise training, the performance improvements follow a non-linear pattern with a relatively faster pace initially and a gradual ‘plateauing-off’ after weeks and months. It is believed that this ‘plateau effect’ is due to a blunting of the molecular responses to acute exercise with exercise training. In the present study we utilised an explorative global transcriptomic approach to investigate the phenomenon of transcriptional-level blunting of the acute exercise response in human skeletal muscle over the course of a three-week HIIT intervention. We hypothesize that the blunting of transcription at this time-point is specific to certain pathways, including metabolic regulation and that these genes have communal transcriptional regulation.
Project description:Exercise is an effective strategy in the prevention and treatment of metabolic diseases. Alterations in the skeletal muscle proteome, including post-translational modifications, regulate its metabolic adaptations to exercise. Here, we examined the effect of high-intensity interval training (HIIT) on the proteome and acetylome of human skeletal muscle, revealing the response of 3168 proteins and 1263 lysine acetyl-sites on 464 acetylated proteins. We identified novel protein adaptations to exercise training involved in metabolism and excitation-contraction coupling. Furthermore, HIIT increased the acetylation of mitochondrial proteins, particularly those of complex V, likely via non-enzymatic mechanisms. We also highlight the regulation of novel exercise-responsive histone acetyl-sites. These data demonstrate the plasticity of the skeletal muscle proteome and acetylome, providing insight into the regulation of contractile, metabolic and transcriptional processes within skeletal muscle. Herein, we provide a substantial hypothesis-generating resource to stimulate further mechanistic research investigating how exercise improves metabolic health.
Project description:The mechanisms underlying exercise-induced effects in the skeletal muscle during cancer cachexia progression have not been fully described. Here, we tested the hypothesis that different exercise training protocols could attenuate metabolic impairment in a severe model of cancer cachexia. Moderate-intensity training (MIT) and high-intensity interval training (HIIT) improved running capacity and prolonged lifespan in tumor-bearing rats. HIIT also reduced oxidative stress and reestablished muscle contractile function. An unbiased proteomics screening revealed that COP9 signalosome complex subunit 2 (COPS2), also known as thyroid receptor interacting protein 15 (TRIP15) or ALIEN, is one of the most downregulated proteins at the early stage of cancer cachexia progression. HIIT restored COPS2/TRIP15/ALIEN protein expression to the control levels. Moreover, lung cancer patients with low endurance capacity had lower muscle COPS2/TRIP15/ALIEN protein content compared to age- and sex-matched control subjects. We further established an in vitro model of cancer-induced muscle wasting using tumor cells-conditioned media to explore the potential protective role of COPS2/TRIP15/ALIEN for myotubes homeostasis. This in vitro model indicate that tumor cells produce factors that directly affect myotube metabolism, but COPS2/TRIP15/ALIEN overexpression is not able to fully reestablish metabolic homeostasis and protein content in myotubes incubated with tumor cells-conditioned media. The current study provides new insight into the role of exercise training as a co-therapy for cancer cachexia and uncovers COPS2/TRIP15/ALIEN as a novel potential target for cancer cachexia.
Project description: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 cut-off 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. Keywords: resistance exercise, muscle, aging
Project description:Skeletal muscle adapts to exercise training of various modes, intensities and durations with a programmed gene expression response. This study dissects the independent and combined effects of exercise mode, intensity and duration to identify which exercise has the most positive effects on skeletal muscle health. Full details on exercise groups can be found in: Kraus et al Med Sci Sports Exerc. 2001 Oct;33(10):1774-84 and Bateman et al Am J Cardiol. 2011 Sep 15;108(6):838-44. This study uses a middle aged group of subjects that have 3+ markers of metabolic syndrome. One group remains an inactive control, while 5 groups undergo 9 mo supervised exercise training. Exercise groups are as follows: Inactive control (group B); Mild aerobic exercise - low amount/mod intensity (group A); Moderate aerobic exercise - low amt/vig intensity (group D); High aerobic exercise - high amt/vig intensity (group C); resistance training only (group F); and mod aerobic + resistance training (group E). Each group has 10 subjects (5 men and 5 women), however 3 subjects failed array QC, leaving 8 subjects in group E and 9 subjects in group F. Data were all analyzed pre to post training in a RM ANCOVA, covaried for age and sex or regression to determine genotype/phenotype interactions.
Project description:The skeletal muscle system plays an important role in the independence of older adults. In this study we examine differences in the skeletal muscle transcriptome between healthy young and older subjects and (pre‐)frail older adults. Additionally, we examine the effect of resistance‐type exercise training on the muscle transcriptome in healthy older subjects and (pre‐)frail older adults. Baseline transcriptome profiles were measured in muscle biopsies collected from 53 young, 73 healthy older subjects, and 61 frail older subjects. Follow‐up samples from these frail older subjects (31 samples) and healthy older subjects (41 samples) were collected after 6 months of progressive resistance‐type exercise training. Frail older subjects trained twice per week and the healthy older subjects trained three times per week. At baseline genes related to mitochondrial function and energy metabolism were differentially expressed between older and young subjects, as well as between healthy and frail older subjects. Three hundred seven genes were differentially expressed after training in both groups. Training affected expression levels of genes related to extracellular matrix, glucose metabolism, and vascularization. Expression of genes that were modulated by exercise training was indicative of muscle strength at baseline. Genes that strongly correlated with strength belonged to the protocadherin gamma gene cluster (r = −0.73). Our data suggest significant remaining plasticity of ageing skeletal muscle to adapt to resistance‐type exercise training. Some age‐related changes in skeletal muscle gene expression appear to be partially reversed by prolonged resistance‐type exercise training. The protocadherin gamma gene cluster may be related to muscle denervation and re‐innervation in ageing muscle.
Project description:A single bout of exercise induces changes in gene expression in skeletal muscle. Regular exercise results in an adaptive response involving changes in muscle architecture and biochemistry, and is an effective way to manage and prevent common human diseases such as obesity, cardiovascular disorders and type II diabetes. Our study is a transcriptome-wide analysis of skeletal muscle tissue in a large cohort of untrained Thoroughbred horses before and after a bout of high-intensity exercise and again after an extended period of training. We hypothesized that regular high-intensity exercise training primes the transcriptome for the demands of high-intensity exercise.