Investigating Isthmin as an adipose-to-muscle messenger that promotes muscle protein synthesis

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ABSTRACT Metabolic stressors and pathologic conditions such as diabetes can lead to pronounced physiologic alterations in protein regulation, resulting in muscle atrophy, which is highly associated with morbidity. However, the mechanisms underlying this association remain elusive. Understanding the mechanisms of maintaining muscle protein content is crucial to improving insulin resistance and overall metabolic health. Adipose tissue is an endocrine organ that responds to acute and chronic energetically challenging conditions by secreting proteins, referred to as adipokines. Evidence suggests that signaling mediated by adipokines plays a crucial role in organ crosstalk and systemic energy metabolism. Because of their direct signaling action, they can be developed as therapeutic agents for metabolic diseases. While considerable effort has been made to target the adipose tissue as a component of insulin resistance, the involvement of adipokines in muscle physiology is understudied. My research training plan will leverage endocrinology, muscle biology, bioinformatics, and newly generated genetic mouse models as a toolkit to investigate the function and mechanisms of a previously understudied hormone in promoting muscle growth with potentially fewer side effects. This proposal tests the central hypothesis that Isthmin-1 (Ism1) mediates adipose-muscle crosstalk that regulates muscle proteostasis. The following aims are proposed: Aim 1: To determine whether Ism1 mediates muscle growth through adipose-muscle crosstalk. Aim 2: To determine whether Ism1 alters balance between muscle protein synthesis and degradation. Aim 3: Using phosphoproteomics to discover novel pathways that regulate muscle proteostasis. If successful, this research will establish a novel adipose-muscle pathway in muscle growth with potential future therapeutic implications, since the Ism1 hormone itself can be used as a direct pharmacologic treatment for atrophy and disorders for which exercise is not an option. This project will also provide training for Dr. Zhao’s long-term goal as an independent investigator to dissect the hormonal crosstalk between metabolic organs to improve metabolic diseases. The candidate Dr. Zhao has extensive and suitable prior training in metabolic physiology, with 13 publications including 5 as first- author since 2016. The Career Development Plan is tailored to enable Dr. Zhao to gain new experimental skills and concepts in muscle biology, biochemistry, and endocrine signaling from expert physiologists, endocrinologists, and biochemists in the mentoring team. The environment at Stanford University is unparalleled for collaborative and innovative research and career development training. In summary, the strong mentoring environment and training plan are anticipated to fully prepare Dr. Zhao to launch her independent career. The proposed studies promise to offer mechanistic insights into adipose-muscle crosstalk to identify therapeutic targets that can counter muscle protein loss and associated metabolic disease.