There are little data from clinical trials in the elderly designed to assess whether the efficacious effects of an intervention are mediated by adaptations in skeletal muscle. The goal of this development project is to implement new assays and to optimize existing methodologies for the analyses of muscle fiber type, capillary density, oxidative enzyme activities, and gene and protein expression in human skeletal muscle, and to apply these methodologies in clinical trials to investigate the molecular mechanisms by which specific therapies increase muscle mass, strength and physical function in older adults. We will conduct muscle biopsies in heart failure patients and in healthy, but functionally limited, elderly adults who are enrolled in three OAIC-supported clinical studies designed to improve physical performance (Pharmacological Intervention in the Elderly; Resistance training in elderly heart failure patients, and Power training in older adults: mechanisms underlying change in muscle function). We will capitalize on the OAIC infrastructure to integrate the expertise of investigators in the Duke and UTMB OAICs to measure muscle fiber diameter, muscle fiber type, capillary density, mitochondrial enzyme activity, mitochondrial gene expression, and protein and gene expression levels of catabolic cytokines from elderly subjects before and after these interventions. This will enable us to increase the number of assays performed, enhance the efficiency of each biopsy sample, and maximize the contributions to knowledge. Application of assays to determine changes in in vitro muscle function to randomized, controlled trials of novel interventions with clinical outcomes such as the proposed studies, as well as future studies, will allow us to begin to better uncover the possible mechanisms by which different therapies lead to increased function in older adults. The research tools and preliminary data garnered as a result of these development resources will provide the necessary information needed to generate new hypotheses and obtain research funding to continue investigation of the skeletal muscle as a target organ for disability and its treatment.
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