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Over the past 20 years, various identifiers of cellular senescence have been used to quantify the abundance of these cells in different tissues. These include classic markers such as p16, senescence-associated β-gal, and γH2AX, in addition to more recent markers (Sudan Black B and HMGB1). In vivo data on the usefulness of these markers in skeletal muscle are very limited and inconsistent. In the present study, we attempted to identify senescent cells in frozen human skeletal muscle biopsies using these markers to determine the effects of age and obesity on senescent cell burden; however, we were only able to assess the abundance of DNA-damaged nuclei using γH2AX immunohistochemistry. The abundance of γH2AX+ cells, including satellite cells, was not higher in muscle from old compared to young individuals; however, γH2AX+ cells were higher with obesity. Additionally, terminally differentiated, postmitotic myofiber nuclei from obese individuals had elevated γH2AX abundance compared to muscle from lean individuals. Analyses of gene expression support the conclusion that the elevated DNA damage and the senescence-associated secretory phenotype are preferentially associated with obesity in skeletal muscle. These data implicate obesity as a larger contributor to DNA damage in skeletal muscle than aging; however, more sensitive senescence markers for human skeletal muscle are needed to determine if these cells are in fact senescent., (© 2020 Federation of American Societies for Experimental Biology.)

We assessed the impact of differing physical activity levels throughout the lifespan, using a musculoskeletal injury model, on the age-related changes in left ventricular (LV) parameters in active mice. Forty male mice (CBA/J) were randomly placed into one of three running wheel groups (transected CFL group, transected ATFL/CFL group, SHAM group) or a SHAM Sedentary group (SHAMSED). Before surgery and every 6 weeks after surgery, LV parameters were measured under 2.5 % isoflurane inhalation. Group effects for daily distance run was significantly greater for the SHAM and lesser for the ATLF/CFL mice (p = 0.013) with distance run decreasing with age for all mice (p < 0.0001). Beginning at 6 months of age, interaction (group × age) was noted with LV posterior wall thickness-to-radius ratios (h/r) where h/r increased with age in the ATFL/CFL and SHAMSED mice while the SHAM and CFL mice exhibited decreased h/r with age (p = 0.0002). Passive filling velocity (E wave) was significantly greater in the SHAM mice and lowest for the ATFL/CFL and SHAMSED mice (p < 0.0001) beginning at 9 months of age. Active filling velocity (A wave) was not different between groups (p = 0.10). Passive-to-active filling velocity ratio (E/A ratio) was different between groups (p < 0.0001), with higher ratios for the SHAM mice and lower ratios for the ATFL/CFL and SHAMSED mice in response to physical activity beginning at 9 months of age. Passive-to-active filling velocity ratio decreased with age (p < 0.0001). Regular physical activity throughout the lifespan improved LV structure, passive filling velocity, and E/A ratio by 6 to 9 months of age and attenuated any negative alterations throughout the second half of life. The diastolic filling differences were found to be significantly related to the amount of activity performed by 9 months and at the end of the lifespan., Competing Interests: Compliance with ethical standards Funding This study was funded by the UNC Charlotte Faculty Research Grants Program. Conflict of interest The authors declare that they have no competing interests.

Aging is accompanied by reduced remodeling of skeletal muscle extracellular matrix (ECM), which is exacerbated during recovery following periods of disuse atrophy. Mechanotherapy has been shown to promote ECM remodeling through immunomodulation in adult muscle recovery, but not during the aged recovery from disuse. In order to determine if mechanotherapy promotes ECM remodeling in aged muscle, we performed single cell RNA sequencing (scRNA-seq) of all mononucleated cells in adult and aged rat gastrocnemius muscle recovering from disuse, with (REM) and without mechanotherapy (RE). We show that fibroadipogenic progenitor cells (FAPs) in aged RE muscle are highly enriched in chemotaxis genes (Csf1), but absent in ECM remodeling genes compared to adult RE muscle (Col1a1). Receptor-ligand (RL) network analysis of all mononucleated cell populations in aged RE muscle identified chemotaxis-enriched gene expression in numerous stromal cell populations (FAPs, endothelial cells, pericytes), despite reduced enrichment of genes related to phagocytic activity in myeloid cell populations (macrophages, monocytes, antigen presenting cells). Following mechanotherapy, aged REM mononuclear cell gene expression resembled adult RE muscle as evidenced by RL network analyses and KEGG pathway activity scoring. To validate our transcriptional findings, ECM turnover was measured in an independent cohort of animals using in vivo isotope tracing of intramuscular collagen and histological scoring of the ECM, which confirmed mechanotherapy-mediated ECM remodeling in aged RE muscle. Our results highlight age-related cellular mechanisms underpinning the impairment to complete recovery from disuse, and also promote mechanotherapy as an intervention to enhance ECM turnover in aged muscle recovering from disuse. [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]

Progressive resistance exercise training (PRT) is the most effective known intervention for combating aging skeletal muscle atrophy. However, the hypertrophic response to PRT is variable, and this may be due to muscle inflammation susceptibility. Metformin reduces inflammation, so we hypothesized that metformin would augment the muscle response to PRT in healthy women and men aged 65 and older. In a randomized, double‐blind trial, participants received 1,700 mg/day metformin (N = 46) or placebo (N = 48) throughout the study, and all subjects performed 14 weeks of supervised PRT. Although responses to PRT varied, placebo gained more lean body mass (p = .003) and thigh muscle mass (p < .001) than metformin. CT scan showed that increases in thigh muscle area (p = .005) and density (p = .020) were greater in placebo versus metformin. There was a trend for blunted strength gains in metformin that did not reach statistical significance. Analyses of vastus lateralis muscle biopsies showed that metformin did not affect fiber hypertrophy, or increases in satellite cell or macrophage abundance with PRT. However, placebo had decreased type I fiber percentage while metformin did not (p = .007). Metformin led to an increase in AMPK signaling, and a trend for blunted increases in mTORC1 signaling in response to PRT. These results underscore the benefits of PRT in older adults, but metformin negatively impacts the hypertrophic response to resistance training in healthy older individuals. ClinicalTrials.gov Identifier: NCT02308228. [ABSTRACT FROM AUTHOR]