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Exercise promotes functional improvements in aged tissues, but the extent to which it simulates partial molecular reprogramming is unknown. Using transcriptome profiling from (1) a skeletal muscle‐specific in vivo Oct3/4, Klf4, Sox2 and Myc (OKSM) reprogramming‐factor expression murine model; (2) an in vivo inducible muscle‐specific Myc induction murine model; (3) a translatable high‐volume hypertrophic exercise training approach in aged mice; and (4) human exercise muscle biopsies, we collectively defined exercise‐induced genes that are common to partial reprogramming. Late‐life exercise training lowered murine DNA methylation age according to several contemporary muscle‐specific clocks. A comparison of the murine soleus transcriptome after late‐life exercise training to the soleus transcriptome after OKSM induction revealed an overlapping signature that included higher JunB and Sun1. Also, within this signature, downregulation of specific mitochondrial and muscle‐enriched genes was conserved in skeletal muscle of long‐term exercise‐trained humans; among these was muscle‐specific Abra/Stars. Myc is the OKSM factor most induced by exercise in muscle and was elevated following exercise training in aged mice. A pulse of MYC rewired the global soleus muscle methylome, and the transcriptome after a MYC pulse partially recapitulated OKSM induction. A common signature also emerged in the murine MYC‐controlled and exercise adaptation transcriptomes, including lower muscle‐specific Melusin and reactive oxygen species‐associated Romo1. With Myc, OKSM and exercise training in mice, as well habitual exercise in humans, the complex I accessory subunit Ndufb11 was lower; low Ndufb11 is linked to longevity in rodents. Collectively, exercise shares similarities with genetic in vivo partial reprogramming. Key points: Advances in the last decade related to cellular epigenetic reprogramming (e.g. DNA methylome remodelling) toward a pluripotent state via the Yamanaka transcription factors Oct3/4, Klf4, Sox2 and Myc (OKSM) provide a window into potential mechanisms for combatting the deleterious effects of cellular ageing.Using global gene expression analysis, we compared the effects of in vivo OKSM‐mediated partial reprogramming in skeletal muscle fibres of mice to the effects of late‐life murine exercise training in muscle.Myc is the Yamanaka factor most induced by exercise in skeletal muscle, and so we compared the MYC‐controlled transcriptome in muscle to Yamanaka factor‐mediated and exercise adaptation mRNA landscapes in mice and humans.A single pulse of MYC is sufficient to remodel the muscle methylome.We identify partial reprogramming‐associated genes that are innately altered by exercise training and conserved in humans, and propose that MYC contributes to some of these responses. [ABSTRACT FROM AUTHOR]

As a consequence of military operations, many veterans suffer from penetrating wounds and long-term retention of military-grade heavy metal fragments. Fragments vary in size and location, and complete surgical removal may not be feasible or beneficial in all cases. Increasing evidence suggests retention of heavy metal fragments may have serious biological implications, including increased risks for malignant transformation. Previous studies assessed the tumorigenic effects of metal alloys in rats, demonstrating combinations of metals are sufficient to induce tumor formation after prolonged retention in skeletal muscle tissue. In this study, we analyzed transcriptional changes in skeletal muscle tissue in response to eight different military-relevant pure metals over 12 mo. We found that most transcriptional changes occur at 1 and 3 mo after metal pellets are embedded in skeletal muscle and these effects resolve at 6 and 12 mo. We also report significant immunogenic effects of nickel and cobalt and suppressive effects of lead and depleted uranium on gene expression. Overall, skeletal muscle exhibits a remarkable capacity to adapt to and recover from internalized metal fragments; however, the cellular response to chronic exposure may be restricted to the metal-tissue interface. These data suggest that unless affected regions are specifically captured by biopsy, it would be difficult to reliably detect changes in muscle gene expression that would be indicative of long-term adverse health outcomes. [ABSTRACT FROM AUTHOR]

Background: The tetracycline-responsive system (Tet-ON/OFF) has proven to be a valuable tool for manipulating gene expression in an inducible, temporal, and tissue-specific manner. The purpose of this study was to create and characterize a new transgenic mouse strain utilizing the human skeletal muscle α-actin (HSA) promoter to drive skeletal muscle-specific expression of the reverse tetracycline transactivator (rtTA) gene which we have designated as the HSA-rtTA mouse. Methods: To confirm the HSA-rtTA mouse was capable of driving skeletal muscle-specific expression, we crossed the HSA-rtTA mouse with the tetracycline-responsive histone H2B-green fluorescent protein (H2B-GFP) transgenic mouse in order to label myonuclei. Results: Reverse transcription-PCR confirmed skeletal muscle-specific expression of rtTA mRNA, while single-fiber analysis showed highly effective GFP labeling of myonuclei in both fast- and slow-twitch skeletal muscles. Pax7 immunohistochemistry of skeletal muscle cross-sections revealed no appreciable GFP expression in satellite cells. Conclusions: The HSA-rtTA transgenic mouse allows for robust, specific, and inducible gene expression across muscles of different fiber types. The HSA-rtTA mouse provides a powerful tool to manipulate gene expression in skeletal muscle. [ABSTRACT FROM AUTHOR]

PURPOSE: Age-related muscle atrophy is a process that naturally occurs during life. Regenerating skeletal muscle to counteract this process can be achieved by resistance training (RT); however, the skeletal muscle hypertrophic response is highly variable across individuals. The molecular underpinnings of this heterogeneity are unclear but likely to include differential muscle gene expression. METHODS: This study explored transcriptional networks linked to RT-induced muscle hypertrophy classified as (1) predictive of hypertrophy, (2) responsive to RT independent of hypertrophy, or (3) plastic (or changes) with hypertrophy. Older adults (n=31, 18F/13M, 70±4y) performed 14-wk RT 3d/wk and muscle hypertrophy was assessed by change in: mid- thigh muscle cross-sectional area (CSA) [computed tomography (CT)], thigh lean mass [dual-energy x-ray absorptiometry (DXA)], and vastus lateralis myofiber CSA [histomorphometry]. Transcriptome-wide poly-A RNA-seq was performed on vastus lateralis tissue collected pre (n=31) and post-RT (n=22). Prediction networks (baseline only) were identified by Weighted Gene Correlation Network Analysis (WGCNA). To identify Plasticity networks, WGCNA change indices for paired samples were calculated and correlated to changes in muscle size outcomes. Pathway-Level Information ExtractoR (PLIER) was applied to identify response networks and link genes to biological annotation. RESULTS: Prediction networks (n=8) confirmed transcripts previously connected to resistance/aerobic training adaptations in the MetaMEx database while revealing novel genes that should fuel future research to understand the influence of baseline muscle gene expression on hypertrophy. Response networks (n=6) indicated RT-induced increase in aerobic metabolism and reduced expression of genes associated with spliceosome biology and type-I myofibers. Fewer Plasticity networks were identified (n=2). CONCLUSION: Findings suggest inter-individual differences in baseline gene expression may contribute more to muscle hypertrophic response heterogeneity than RT-induced changes. Investigation of factors (e.g., epigenomic) modulating baseline gene expression profiles are of great interest for future studies. Supported by: R01AG046920, U01AR071133, P2CHD086851, and F32AG062048. [ABSTRACT FROM AUTHOR]