Mtorc1 Sensitivity To Amino Acids In Skeletal Muscle And Myotubes Derived From Young And Older Men

Abstract

Ageing is associated with a progressive loss of muscle mass termed sarcopenia, increasing morbidity and mortality. Although multifactorial in nature, dysregulated sensing of amino acids (AAs) after nutrient ingestion, coupled with blunted mTORC1 activation and muscle protein synthesis (MPS), is undoubtedly a major contributing factor in the development and progression of sarcopenia. However, it is unknown whether this is a result of poor AA delivery to the muscle or diminished AA sensing intrinsic to aged muscle cells. Exercise has been shown to increase the sensitivity of muscle to AAs, and conversely, reductions in physical activity appear to drastically impair this response. Since there is typically a reduction in habitual physical activity in the elderly, the impaired muscle growth response to AAs may be a consequence of a lack of physical activity rather than ageing. PURPOSE: To determine the roles that age and physical activity levels play in the activation of anabolic pathways within skeletal muscle and myotube cultures in response to AAs. METHODS: A cross-sectional study was used to compare mTORC1 signaling in response to ingestion of whey protein in 7 young active (Y, 23±2 yrs), 8 older active (OA, 71±4 yrs) and 3 older inactive (OI, 71±5 yrs) men. To determine if mTORC1 sensitivity is intrinsically regulated and remembered by skeletal muscle cells, myoblasts were isolated from biopsies from these participants and differentiated to form myotubes. Myotube cultures were then deprived of serum and AAs, re-stimulated with AAs, and subsequently lysed temporally for mTORC1 analysis. RESULTS: Our preliminary data indicates that phosphorylation of ribosomal protein s6 (RPS6), a downstream mTORC1 substrate, was increased in myotube cultures from Y and OA men with a reduced response in OI men (Y= 7.2 + 7.3, AO= 9.8 + 4.5, IO = 6.0 + 5.6 -fold). We are currently analysing muscle tissue from these same individuals to understand if mTORC1 signaling is comparable between biopsy tissue and myotube cultures. CONCLUSION: Sustained physical activity levels in older individuals and regular structured exercise may diminish age-related mTORC1 desensitisation of skeletal muscle in response to AA ingestion in cultured myotubes.