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In the last few years, single cell and single nucleus RNA-sequencing technologies have been leveraged in exercised adult skeletal muscle to reveal complex cell type-specific regulation of muscle plasticity. Expanding -omics technology at single cell resolution, complimented by advanced computational approaches, promise to rapidly accelerate our understanding of how exercise confers its numerous beneficial effects, paving the way for cell type-specific and targeted therapeutics to increase exercise responses during aging and in the face of chronic disease. [ABSTRACT FROM AUTHOR]

Background: Pax7+ satellite cells are required for skeletal muscle fiber growth during post-natal development in mice. Satellite cell-mediated myonuclear accretion also appears to persist into early adulthood. Given the important role of satellite cells during muscle development, we hypothesized that the necessity of satellite cells for adaptation to an imposed hypertrophic stimulus depends on maturational age. CreER DTA Methods: Pax7 -R26R mice were treated for 5 days with vehicle (satellite cell-replete, SC+) or tamoxifen (satellite cell-depleted, SC-) at 2 months (young) and 4 months (mature) of age. Following a 2-week washout, mice were subjected to sham surgery or 10 day synergist ablation overload of the plantaris (n =6-9 per group). The surgical approach minimized regeneration, de novo fiber formation, and fiber splitting while promoting muscle fiber growth. Satellite cell density (Pax7+ cells/fiber), embryonic myosin heavy chain expression (eMyHC), and muscle fiber cross sectional area (CSA) were evaluated via immunohistochemistry. Myonuclei (myonuclei/100 mm) were counted on isolated single muscle fibers. Results: Tamoxifen treatment depleted satellite cells by ≥90% and prevented myonuclear accretion with overload in young and mature mice (p < 0.05). Satellite cells did not recover in SC- mice after overload. Average muscle fiber CSA increased ~20% in young SC+ (p = 0.07), mature SC+ (p < 0.05), and mature SC- mice (p < 0.05). In contrast, muscle fiber hypertrophy was prevented in young SC- mice. Muscle fiber number increased only in mature mice after overload (p < 0.05), and eMyHC expression was variable, specifically in mature SC+ mice. Conclusions: Reliance on satellite cells for overload-induced hypertrophy is dependent on maturational age, and global responses to overload differ in young versus mature mice. [ABSTRACT FROM AUTHOR]

Background: Muscle mass and strength are strong determinants of a person's quality of life and functional independence with advancing age. While resistance training is the most effective intervention to combat age-associated muscle atrophy (sarcopenia), the ability of older adults to increase muscle mass and strength in response to training is blunted and highly variable. Thus, finding novel ways to complement resistance training to improve muscle response and ultimately quality of life among older individuals is critical. The purpose of this study is to determine whether a commonly prescribed medication called metformin can be repurposed to improve the response to resistance exercise training by altering the muscle tissue inflammatory environment.Methods/design: Individuals aged 65 and older are participating in a two-site, randomized, double-blind, placebo-controlled trial testing the effects of metformin or placebo on muscle size, strength, and physical function when combined with a progressive resistance training program. Participants consume 1700 mg of metformin per day or placebo for 2 weeks before engaging in a 14-week progressive resistance training regimen, with continued metformin or placebo. Participants are then monitored post-training to determine if the group taking metformin derived greater overall benefit from training in terms of muscle mass and strength gains than those on placebo. Muscle biopsies are taken from the vastus lateralis at three time points to assess individual cellular and molecular adaptations to resistance training and also changes in response to metformin.Discussion: The response of aged muscles to a resistance training program does not always result in a positive outcome; some individuals even experience a loss in muscle mass following resistance training. Thus, adjuvant therapies, including pharmacological ones, are required to optimize response to training in those who do not respond and may be at increased risk of frailty. This is the first known metformin repurposing trial in non-diseased individuals, aimed specifically at the resistance exercise "non-responder" phenotype present in the aging population. The overall goal of this trial is to determine if combined exercise-metformin intervention therapy will benefit older individuals by promoting muscle hypertrophy and strength gains, thereby maintaining functional independence.Trial Registration: ClinicalTrials.gov, NCT02308228 . Registered on 25 November 2014. [ABSTRACT FROM AUTHOR]

Background: Immune function may influence the ability of older adults to maintain or improve muscle mass, strength, and function during aging. Thus, nutritional supplementation that supports the immune system could complement resistance exercise as an intervention for age-associated muscle loss. The current study will determine the relationship between immune function and exercise training outcomes for older adults who consume a nutritional supplement or placebo during resistance training and post-training follow-up. The supplement was chosen due to evidence suggesting its ingredients [arginine (Arg), glutamine (Gln), and β-hydroxy β-methylbutyrate (HMB)] can improve immune function, promote muscle growth, and counteract muscle loss. Methods/design: Veterans (age 60 to 80 yrs, N = 50) of the United States military will participate in a randomized double-blind placebo-controlled trial of consumption of a nutritional supplement or placebo during completion of three study objectives: 1) determine if 2 weeks of supplementation improve immune function measured as the response to vaccination and systemic and cellular responses to acute resistance exercise; 2) determine if supplementation during 36 sessions of resistance training boosts gains in muscle size, strength, and function; and 3) determine if continued supplementation for 26 weeks post-training promotes retention of training-induced gains in muscle size, strength, and function. Analyses of the results for these objectives will determine the relationship between immune function and the training outcomes. Participants will undergo nine blood draws and five muscle (vastus lateralis) biopsies so that the effects of the supplement on immune function and the systemic and cellular responses to exercise can be measured. Discussion: Exercise has known effects on immune function. However, the study will attempt to modulate immune function using a nutritional supplement and determine the effects on training outcomes. The study will also examine post-training benefit retention, an important issue for older adults, usually omitted from exercise studies. The study will potentially advance our understanding of the mechanisms of muscle gain and loss in older adults, but more importantly, a nutritional intervention will be evaluated as a complement to exercise for supporting muscle health during aging. [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]