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Myogenic progenitors in adult muscle are necessary for the repair, maintenance and hypertrophy of post-mitotic muscle fibers. With age, fat deposition and fibrosis contribute to the decline in the integrity and functional capacity of muscles. In a previous study we reported increased accumulation of lipid in myogenic progenitors obtained from aged mice, accompanied by an up-regulation of genes involved in adipogenic differentiation. The present study was designed to extend our understanding of how aging affects the fate and gene expression profile of myogenic progenitors. Affymetrix murine U74 Genechip analysis was performed using RNA extracted from myogenic progenitors isolated from adult (8-month-old) and aged (24-month-old) DBA/2JNIA mice. The cells from the aged animals exhibited major alterations in the expression level of many genes directly or indirectly involved with the TGFbeta signaling pathway. Our data indicate that with age, myogenic progenitors acquire the paradoxical phenotype of being both TGFbeta activated based on overexpression of TGFbeta-inducible genes, but resistant to the differentiation-inhibiting effects of exogenous TGFbeta. The overexpression of TGFbeta-regulated genes, such as connective tissue growth factor, may play a role in increasing fibrosis in aging muscle.

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]

Resistance exercise (RE) induces a cytokine response in muscle that is involved with repair and possibly adaptive processes that may be impaired by aging. Specifically, median IL-1β mRNA levels were elevated 72 hrs post-RE in v. lateralis from young (Y), but not elderly (E) males. The lack of a response in the E appeared due to chronic elevation of IL-1β (Exp Gerontol 41:3, 320-327). Under these circumstances, IL-1β was hypothesized to control genes expressed in the myofiber that are relevant to growth and atrophy. To identify candidate genes, 100 mRNAs were screened using a custom real-time PCR method of which 15 were chosen and quantified for Y (N=15, 31.7 ± 7.4 yrs) and E (N=16, 71.6 ± 4.6) pre- and post-RE. Between groups, the Y possessed greater (1.6 to 4.4-fold) IGF1, CNTF, MMP2, and IGFBP5 at both time points. Of these, MMP2 was the only one responsive to exercise and this 1.5-fold increase was exclusive to the E. Other mRNAs responded to exercise in both Y and E but the magnitudes and significances were greater for Y. In the Y, TIMP1 and ACTC1 increased 2-fold and 6.5-fold, whereas GDF8 decreased 50%. In the E, TIMP1 and ACTC1 expression only increased 1.2-fold and 2.9-fold, whereas GDF8 decreased 40%. Work is underway to determine the cellular source, response to IL-1β, and functional significance to aging and RE for these factors in muscle. Stated differences were significant at P<0.05. [ABSTRACT FROM AUTHOR]