The loss of skeletal muscle mass, strength, and physical function with age (sarcopenia) has numerous physiological and metabolic consequences that may lead to undesirable outcomes in older adults. Skeletal muscle plays a direct role in force production and its loss can lead to reduced mobility, loss of balance, increased incidence of falls and ultimately disability and loss of independence. In addition, muscle plays an underappreciated role in metabolism and sarcopenia has been associated with insulin resistance and metabolic syndrome. Consequently, identifying interventions that maintain muscle mass and function is a high priority therapeutic goal to improve quality of life and reduce medical costs associated with older adult populations. Dietary intake of the branch-chained amino acid leucine increases the rate of protein synthesis in skeletal muscle through mechanistic target of rapamycin complex 1 (mTORC1)-dependent as well as independent signaling pathways. However, physical inactivity reduces the ability to stimulate muscle protein synthesis in response to amino acids, termed anabolic resistance. Since older adults are at a greater risk of being inactive due to injury, illness or sedentary behavior, it is thought that anabolic resistance to amino acids may contribute to the development of sarcopenia. One barrier to progress in this field is that while the ability of leucine to activate protein synthesis is well known, little is known about how activation of these pathways differentially controls the translation of specific mRNAs to support the anabolic effects of leucine, or how these changes in gene expression may vary in individuals with anabolic resistance. Here we propose to define the leucine-induced translation program in skeletal muscle of older adults in response to inactivity-induced anabolic resistance using ribosome profiling and RNA-Seq. We will further analyze mRNA-specific ribosome coverage patterns, as well as monitor changes in expression of muscle- specific miRNAs, transcription factors, and RNA-binding proteins to develop hypotheses regarding the mechanisms involved in leucine-induced regulation of translation and mRNA abundance. The identification of the genes and pathways affected by leucine ingestion in older individuals with anabolic resistance as well as the mechanisms involved will provide critical information to rationalize new studies aimed at therapeutic interventions designed to prevent or offset the development of sarcopenia.
Sarcopenia, the loss of skeletal muscle mass, strength, and function with age, has numerous physiological and metabolic consequences that may lead to undesirable outcomes in older adults. Reduced ability to stimulate muscle protein synthesis in response to leucine in physically inactive older adults may be an underlying factor of sarcopenia. The broad objectives of this proposal are to define the leucine-induced translation program in skeletal muscle of individuals before and after inactivity-induced anabolic resistance and to identify differences in the genes and pathways affected in order to rationalize further studies aimed at therapeutic interventions to prevent or offset the development of sarcopenia
