Loss of muscle mass is common in many clinical conditions such as cancer, AIDS, burns and paralysis as well as in aging. Decreased muscle mass can contribute to many other complications and co-morbidities related to diseases, trauma and aging including overall weakness, immobility, increased risk of falls, impaired stress response and metabolic dysfunction. Nutrition and resistance exercise are two readily available and extremely anabolic stimuli for skeletal muscle, though their specific cellular mechanisms remain largely unknown. Studies were designed to examine the mammalian target of rapamycin (mTOR) muscle hypertrophy pathway in conditions of differing physical activity levels, to determine the effects of low and high carbohydrate and insulin levels (combined with essential amino acids) on protein turnover and cellular signaling following resistance exercise, and to investigate similar parameters in response to various combinations of anabolic nutrients. Stable isotopic techniques with arterial/venous catheterization and muscle biopsies, immunoprecipitation and immunoblotting, quantitative real-time PCR and hormone (ELISA) assays were utilized to examine muscle protein turnover, cellular signaling pathways, mRNA expression related to proteins of interest and hormonal responses, respectively. The main findings from these studies were that increased physical activity downregulated the mTOR signaling pathway and decreased inhibitory phosphorylation of insulin receptor substrate 1 (IRS-1). In contrast, mTOR activity may play an important role in paraplegia-induced muscle atrophy as 10 weeks of paraplegia in rats significantly downregulated the mTOR pathway. In humans and compared to modest carbohydrate ingestion, higher amounts of carbohydrate and consequent increases in circulating insulin were unable to further reduce muscle protein breakdown, associated signaling or mRNA expression following a bout of resistance exercise. Similarly, increasing concentrations of leucine may not provide any additional benefit to net protein balance, as has been previously proposed. These studies further our understanding of muscle hypertrophy and atrophy, and begin to provide the scientific data necessary in order to establish evidence-based recommendations for the maintenance of skeletal muscle mass during conditions of muscle wasting.