David J. Kosek

Heightened muscle inflammation susceptibility may impair regenerative capacity in aging humans

The regenerative response of skeletal muscle to mechanically induced damage is impaired with age. Previous work in our laboratory suggests this may result from higher proinflammatory signaling in aging muscle at rest and/or a greater inflammatory response to damage. We, therefore, assessed skeletal muscle proinflammatory signaling at rest and 24 h after unaccustomed, loaded knee extension contractions that induced modest muscle damage (72% increase in serum creatine kinase) in a cohort of 87 adults across three age groups (AGE40, AGE61, and AGE76). Vastus lateralis muscle gene expression and protein cell signaling of the IL-6 and TNF-α pathways were determined by quantitative PCR and immunoblot analysis. For in vitro studies, cell signaling and fusion capacities were compared among primary myoblasts from young (AGE28) and old (AGE64) donors treated with TNF-α. Muscle expression was higher (1.5- to 2.1-fold) in AGE76 and AGE61 relative to AGE40 for several genes involved in IL-6, TNF-α, and TNF-like weak inducer of apoptosis signaling. Indexes of activation for the proinflammatory transcription factors signal transducer and activator of transcription-3 and NF-κB were highest in AGE76. Resistance loading reduced gene expression of IL-6 receptor, muscle RING finger 1, and atrogin-1, and increased TNF-like weak inducer of apoptosis receptor expression. Donor myoblasts from AGE64 showed impaired differentiation and fusion in standard media and greater NF-κB activation in response to TNF-α treatment (compared with AGE28). We show for the first time that human aging is associated with muscle inflammation susceptibility (i.e., higher basal state of proinflammatory signaling) that is present in both tissue and isolated myogenic cells and likely contributes to the impaired regenerative capacity of skeletal muscle in the older population.

Modulation of the dystrophin-associated protein complex in response to resistance training in young and older men

The dystrophin-associated protein complex (DAPC) is a scaffold of proteins linking the intracellular cytoskeleton with the extracellular matrix that is integral to structural stability and integrity, signaling and mechanotransduction, and force transmission. We hypothesized that the expression of DAPC component proteins would be altered by resistance loading during progressive resistance training (PRT)-mediated myofiber hypertrophy, and we investigated whether aging influenced these changes. Seventeen young (27 yr) and 13 older (65 yr) men completed 16 wk of PRT with muscle biopsies at baseline (T1), 24 h after bout 1 (T2), and 24 h after the final bout at week 16 (T3). Myofiber hypertrophy in the young (type I 31%, P < 0.005; type II 40%, P < 0.001) far exceeded hypertrophy in the old (type II only, 19.5%, P < 0.05). PRT altered protein expression for caveolin-3 (decreased 24% by T3, P < 0.01), alpha(1)-syntrophin (increased 16% by T3, P < 0.05), alpha-dystrobrevin (fell 23% from T2 to T3, P < 0.01), and dystrophin [rose acutely (30% by T2, P < 0.05) and returned to baseline by T3]. The phosphorylation state of membrane neuronal nitric oxide synthase (Ser(1417)) decreased 70% (P < 0.005) by T3, particularly in the old (81%), whereas p38 MAPK phosphorylation increased twofold by T3 in the old (P < 0.01). We conclude that component proteins of the DAPC are modulated by PRT, which may serve to improve both structural and signaling functions during load-mediated myofiber hypertrophy. The blunted hypertrophic adaptation seen in old vs. young men may have resulted from overstress, as suggested by marked p38 MAPK activation in old men only.

Human neuromuscular aging: Sex differences revealed at the myocellular level

&NA; Age‐related muscle loss (sarcopenia) is a major clinical problem affecting both men and women – accompanied by muscle weakness, dysfunction, disability, and impaired quality of life. Current definitions of sarcopenia do not fully encompass the age‐related changes in skeletal muscle. We therefore examined the influence of aging and sex on elements of skeletal muscle health using a thorough histopathological analysis of myocellular aging and assessments of neuromuscular performance. Two‐hundred and twenty‐one untrained males and females were separated into four age cohorts [mean age 25 y (n = 47), 37 y (n = 79), 61 y (n = 51), and 72 y (n = 44)]. Total (−12%), leg (−17%), and arm (−21%) lean mass were lower in both 61 y and 72 y than in 25 y or 37 y (P < 0.05). Knee extensor strength (−34%) and power (−43%) were lower (P < 0.05) in the older two groups, and explosive sit‐to‐stand power was lower by 37 y (P < 0.05). At the histological/myocellular level, type IIx atrophy was noted by 37 y and type IIa atrophy by 61 y (P < 0.05). These effects were driven by females, noted by substantial and progressive type IIa and IIx atrophy across age. Aged female muscle displayed greater within‐type myofiber size heterogeneity and marked type I myofiber grouping (˜5‐fold greater) compared to males. These findings suggest the predominant mechanisms leading to whole muscle atrophy differ between aging males and females: myofiber atrophy in females vs. myofiber loss in males. Future studies will be important to better understand the mechanisms underlying sex differences in myocellular aging and optimize exercise prescriptions and adjunctive treatments to mitigate or reverse age‐related changes.