Activity-dependent signaling in aging skeletal muscle

Tufts University Boston, Boston MA

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Abstract

DESCRIPTION (provided by applicant): The age-related loss of skeletal muscle mass is associated with well-characterized functional limitations and physical disability. Although resistance training attenuates age-related muscle loss, the cellular processes that initiate muscle hypertrophy and the extent to which they are preserved with age are not well understood. The 70-kDa S6 protein kinase (p70S6K) is a downstream target of the protein kinase B/mammalian target of rapamycin (Akt/mTOR) pathway that has been implicated in the regulation of muscle size during overload and disuse atrophy. This and other kinases of the Akt/mTOR pathway affect protein translation by regulating translational inhibitors such as glycogen synthase kinase 3 (GSK-3), phosphorylating key ribosomal proteins, and influencing the availability of eukaryotic initiation factors (elF's). We propose to test the hypotheses that 1) aging is associated with a reduced activation of the Akt/mTOR pathway 2) the reduced phosphorylation of p70S6K and mTOR results in a decreased number of elF4E-elF4G complexes and a reduction in muscle protein synthesis, and 3) chronic contractile activity results in blunted muscle hypertrophy in older animals due to a reduced activation of the Akt/mTOR pathway. We propose to use electrical stimulation to simulate acute resistance exercise in young and old rat hindlimbs, and surgical ablation of synergistic muscles to model the effects of chronic contractile activity. Specifically, we will 1) characterize Akt/mTOR signaling after a single bout of resistance exercise at young age, 2) assess the effects of resistance exercise on the number of capped mRNA binding sites (elF4E-elF4G) available for protein translation at young age, 3) compare the activation of Akt/mTOR, formation of elF4E-elF4G complexes, and protein synthesis of young, middle aged, and old rats in response to acute contractile activity, 4) compare the activation of Akt/mTOR, formation of elF4E-elF4G, and protein synthesis of young, middle aged, and old rats in response to chronic ablation of synergistic muscles. Muscle samples at several time points will be analyzed for p70S6K, Akt, mTOR, 4EBP1, and GSK-3 phosphorylation, elF4E-elF4G complexes, and skeletal muscle protein synthesis. We believe that the identification of molecular dysregulation in the Akt/mTOR pathway associated with age-related muscle atrophy will establish the groundwork for studies aimed at correcting these deficiencies and improving the efficacy of resistance training and other therapeutic interventions in the elderly.