Identifying therapeutic targets of accelerated sarcopenia
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DESCRIPTION (provided by applicant): Sarcopenia is a major contributor to frailty and increases the risk of falls, physical dependence, disability and mortality in older adults. It advances slowly with healthy aging. However, diseases or other insults and injuries can accelerate sarcopenia and lead to catastrophic declines in mobility and independence. For example, chronic diseases such as Type 2 Diabetes Mellitus (T2DM) are associated with accelerated loss of muscle mass and function in seniors; hospitalization with bed rest inactivity acutely accelerates sarcopenia. What we do not know is how concurrent diseases, inactivity or other insults and injuries accelerate sarcopenia in older adults. This knowledge gap hinders the development of innovative, targeted treatments for this disabling condition. Our objective is to examine the basic mechanisms that underlie accelerated sarcopenia in older adults and identify potential targets for interventions. The central hypothesis, based on our preliminary data, is that a global and fundamental mechanism of acute or chronic acceleration of sarcopenia is a reduction in skeletal muscle amino acid transport, which decreases muscle protein anabolism, and can be reversed by activation of the mammalian/mechanistic Target of Rapamycin Complex 1 (mTORC1) signaling with a non- amino acid stimulus such as exercise. Amino acid transport is an active process that controls intracellular amino acid availability and the activation of protin synthesis in skeletal muscle. It is regulated by amino acid concentrations and non-amino acid stimuli that activate mTORC1 signaling, such as resistance exercise and insulin. We will test our central hypothesis with the following specific aims: 1) Determine the effect of T2DM on the sensitivity of skeletal muscle amino acid transport to dietary amino acids. 2) Determine the effect of short-term bed rest inactivity on the sensitivity of skeletal muscle amino acid transport to dietary amino acids. 3) Determine the effect of resistance exercise on the sensitivity of amino acid transport to dietary amino acids in acute and chronic accelerated sarcopenia induced by inactivity and T2DM. Using integrative molecular, imaging and stable isotope methodologies we will measure amino acid transport and protein metabolism in muscle, identifying specific upstream regulators involved in the anabolic resistance of accelerated sarcopenia that can be targeted with novel treatments to reduce sarcopenia and improve independence in older adults.
