Roger A. Fielding - US grants

DESCRIPTION (provided by applicant): This proposal is for the competitive renewal of RO1 AG018844, which is in its third year of funding and is submitted in response to PAS-03-122 "Frailty in Old Age: Pathophysiology and Interventions". The focus of this research has been to examine the physiologic and functional effects of a muscle power training intervention in comparison to traditional progressive resistance training in a community-based group of elderly men and women with moderate mobility limitations. During the current project period, we have successfully demonstrated that peak lower extremity power is closely associated with functional limitations and self-reported disability in older community dwelling men and women. We propose to extend our previous findings by examining the physiological mechanisms that contribute to the age and gender-related declines in peak muscle power. To compliment our existing data on skeletal muscle fiber contractile properties, we will assess the neural contributions to the generation of muscle power with advancing age. We will test the hypothesis that skeletal muscle single fiber contractile properties (i.e. single fiber power, shortening velocity, specific force), neural factors (i.e. intermuscular coordination patterns, central activation ratios/and motor unit control properties) and lower extremity power will be reduced with advancing age and degree of risk for mobility disability, and these differences will be attenuated in women compared to men. Middle-aged healthy (40-55 yrs.), older healthy (70-85 yrs), and older (70-85 yrs) men and women at risk for mobility disability will be studied under controlled conditions (Study 1). In addition, in light of our recent observations that differences in lower extremity maximal velocity occur at relatively low external forces (eg: 40% 1 RM) and are most closely associated with gait velocity in older individuals, we propose conducting a randomized controlled trial of high velocity low resistance exercise training in individuals at risk for mobility disability to test the hypothesis that a short-term resistance training intervention performed against a low external force and at maximum voluntary velocity will induce significant reductions in mobility disability as evidenced by improvements in gait velocity during performance of a 400 M walk in older individuals at risk for mobility disability (SPPB score <_9, 70 - 85 yrs) (Study 2). The results of these studies will have important implications in understanding the proximal determinants of physical disability in the frail elderly and in designing intervention strategies targeted at improving mobility.

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.