Study examining lifelong wheel running exercise and mild caloric restriction. Skeletal muscle atrophy progressed rapidly in microgravity with 10-20% mass loss within first month. Type I slow-twitch fibers were preferentially affected. Protein synthesis decreased while proteolytic pathways upregulated. Myosin heavy chain isoforms shifted toward faster phenotypes. Exercise countermeasures attenuated but did not prevent muscle loss. Mitochondrial function declined with reduced oxidative capacity.