This study proposes to investigate how myostatin regulates skeletal muscle energy utilization. Myostatin (Mst) is a secreted protein that belongs to the transforming growth factor beta (TGF-2) family;it regulates skeletal muscle mass, modulates transcription of muscle-specific genes, maintains muscle satellite cells in a quiescent state, and inhibits muscle regeneration, proliferation and differentiation during embryogenesis. Limited data are available exploring the role of Mst in regulation of total body composition (muscle and fat mass) during adolescence and adulthood. We recently generated a conditional Mst over expressing transgenic (CMOT) mouse in which the transgene can be turned-ON and -OFF by doxycycline at will. The innovative hypothesis of the current proposal is that during adulthood, Mst plays a role in determining skeletal muscle carbohydrate utilization, fiber type composition, physical performance, and body composition including muscle and fat mass. Understanding molecular signaling pathways behind these effects will shift our current view of Mst as a negative regulator of muscle mass towards that Mst has an integrated and well coordinated role with other regulatory factors in energy expenditure in adult skeletal muscle. We will test this hypothesis by pursuing the following specific aims using four animal models that differ in Mst expression times and levels: 1) Mst transgenic;2) CMOT;3) Mst knock-out;and 4) wild type mice.
Specific Aim 1. To determine the role of Mst in muscle structure, contractility and physical performance using exercise test model: Outcomes will include: force-velocity relationship, maximal exercise tolerance as measured by VO2max, maximal running speed and the endurance will be characterized by the running speed- endurance curves, as well as mitochondrial function, changes in muscle morphology and in gene expression in male and female adult mice.
Specific Aim 2. To investigate the effect of carbohydrate diets on muscle metabolism: A combined effect of high or low carbohydrate diet and differential Mst expression will be investigated on muscle function in male and female adult mice.
Specific aim 3. To analyze the effect of a high fat diet on the process of fat accumulation and cross- communication between muscle and fat tissues: The effects of high fat diet will be analyzed by body composition, muscle performance, exercise tolerance, muscle and fat tissues structure/function in Mst over expressing adult mice. The mechanism by which Mst influences obesity and/or the metabolic syndrome will be identified. Mst and/or its downstream effectors are regarded as potential targets for the development of promyogenic drugs for the treatment of muscle wasting and prevention of obesity. This study will focus on Mst function in adulthood and will enhance our understanding of the regulatory role of Mst and may additionally provide insight into the treatment of muscle loss and metabolic syndrome.

Public Health Relevance

This project will investigate how myostatin affects adult skeletal muscle energy expenditure and fat accumulation. Chronic inactivity and a sedentary lifestyle deconditions muscle for ambulation, making physical activity difficult and unpleasant. Loss of muscle strength and endurance contribute to a progressive loss of physical function, fat accumulation and obesity. Obesity and type 2 diabetes are becoming increasingly common in both adults and children, but the underlying mechanisms are poorly understood. The inverse association between physical activity and obesity is well established, and lifestyle intervention studies show that exercise dramatically reduces the risk of developing the disease. This project will investigate myostatin's role in the cross talk between muscle and adipose tissue in the adult.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Enhancement Award (SC1)
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Special Emphasis Panel (ZGM1-MBRS-X (NP))
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Zlotnik, Hinda
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Charles R. Drew University of Medicine & Science
Other Basic Sciences
Schools of Allied Health Profes
Los Angeles
United States
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