Regulation of Muscle Protein Phenotype in Humans with Obesity - Resubmission - 1

Regulation of Muscle Protein Phenotype in Humans with Obesity - Resubmission - 1 Regulation of Muscle Protein Phenotype in Humans with Obesity Obesity is increasing in the developed world, and more than one-third of the adult population (35%) in the United States are classified as obese. When compared to lean humans, humans with obesity demonstrate differential expression of proteins in skeletal muscle. Differential expression of skeletal muscle myosin heavy chain (MHC) protein isoforms, which collectively determine the MHC proteome in skeletal muscle, is a hallmark of distorted muscle proteome in humans with obesity. The content of the MHC-I isoform is characteristically low, whereas that of MHC-IIx is high, in skeletal muscle of humans with obesity, resulting in an unfavorable muscle MHC proteome phenotype that has been consistently linked to obesity-associated adverse metabolic and functional outcomes. These MHC-specific proteome alterations in muscle of humans with obesity are resistant to weight-loss interventions, indicating an apparent inflexibility in modifying the MHC proteome in muscle of humans with obesity, and with life-long physiological and clinical implications. We will determine rates of synthesis and breakdown of the overall proteome in skeletal muscle of humans with obesity and lean controls, along with relevant molecular mechanisms regulating these processes in muscle. We will focus specifically on the rates of synthesis and breakdown of MHC isoforms, as well as gene expression of the MHC isoforms. That way, we will be able to obtain a deeper insight on the biology that sustains the unfavorable MHC proteome phenotype in muscle of humans with obesity. A prerequisite for muscle MHC proteome remodeling in humans with obesity is an increase in the content of the MHC-I isoform, which is physiologically achieved by increase in the rate of synthesis of MHC-I. Acute aerobic exercise provides the muscle with a stimulus to increase MHC-I transcription, while acute increase in plasma amino acids is a powerful signal to upregulate overall protein translation in muscle. Consequently, by employing acute aerobic exercise and increase in plasma amino acids as investigational tools to target biological processes of transcription and translation, respectively, that regulate the rate of synthesis of MHC-I in muscle we expect to understand the underlying biological mechanisms responsible for distorted MHC proteome in muscle of humans with obesity. Overall, these studies will investigate the mechanistic underpinnings responsible for disrupted muscle proteome homeostasis in skeletal muscle of humans with obesity. Findings from the proposed studies will provide an understanding particularly of the factors that sustain unfavorable MHC proteome in muscle of humans with obesity. Furthermore, these findings may provide novel targets for interventions that can favorably remodel the muscle proteome in obesity to improve metabolism and function in skeletal muscle of humans with obesity. Regulation of Muscle Protein Phenotype in Humans with Obesity-Diversity Supplement