Muscle atrophy is a prominent and debilitating medical condition in humans, but the signaling molecules that initiate this process have not been elucidated yet. Our goal is to identify novel molecule(s) that regulate pathways involved in protein synthesis and/or protein degradation, leading to regulation of muscle mass. We hypothesize in this study that TRB3 mediates denervation-induced skeletal muscle atrophy and that inhibition of TRB3 ameliorates the loss of muscle mass. This hypothesis has been formulated on the basis of preliminary data showing that TRB3 expression is induced by muscle denervation and that overexpression of TRB3 inhibits Akt activity. Furthermore, knockout of TRB3 in mice results in increased Akt activity and decreased FOXO function. We will test the hypothesis by pursing two specific aims.
In Aim 1, we will determine TRB3 expression and function in response to skeletal muscle denervation. Under this aim, we will overexpress TRB3 in skeletal muscle using electroporation technique and muscle-specific TRB3 transgenic mice, and assess the denervation-induced muscle atrophy. Guided by our preliminary data, we anticipate that overexpression of TRB3 in muscle will worsen muscle atrophy.
In Aim 2, we will determine if TRB3 inhibition prevents denervation-induced skeletal muscle atrophy. To this end, we will study TRB3 knockout mice to determine if the mice are resistant to denervation-induced muscle mass loss. We will also determine protein synthesis and Akt activity in the knockout mice. We expect that knockout of TRB3 will prevent mice from developing denervation-induced muscle atrophy through ablation of decreases in protein synthesis and Akt activity in response to muscle denervation. The proposed research will establish the novel function of TRB3 on muscle atrophy and identify a new approach for treating muscle atrophy. In addition, the study will provide evidence to investigate the role of TRB3 in other muscle diseases related to muscle atrophy, including muscle disuse, cachexia, and sarcopenia. The study will be innovative in 1) proposing new insight into the cellular and molecular etiology of muscle atrophy development; 2) studying unique animals that model both Gain-of- function (TRB3 transgenic mice) and Loss-of-function (TRB3 knockout mice); and 3) investigating a novel function of TRB3 on muscle mass regulation. The proposed study will be also significant in providing new insights into the pathogenesis of muscle atrophy and in holding promise for the development of pharmacological agents that could prevent muscle atrophy during a wide range of diseased states. Furthermore, the knowledge that we will gain from this project can be applied to other muscle diseases that are directly or indirectly related to muscle atrophy.

Public Health Relevance

The loss of muscle mass (atrophy) is one of the medical consequences of many diseases, including cancer, neurodegenerative diseases and autoimmune diseases, and results in serious health problems. The exact causes of muscle atrophy are not known, and this study will investigate the role that a protein, TRB3, may play in mediating one type of muscle loss. Better understanding muscle atrophy and the proteins that affect it may lead to the development of new drugs to treat atrophy and its complications.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Small Research Grants (R03)
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Special Emphasis Panel (ZAR1)
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Cheever, Thomas
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University of South Carolina at Columbia
Other Health Professions
Schools of Public Health
United States
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Choi, Ran Hee; McConahay, Abigail; Jeong, Ha-Won et al. (2017) Tribbles 3 regulates protein turnover in mouse skeletal muscle. Biochem Biophys Res Commun 493:1236-1242
Koh, Ho-Jin (2016) Regulation of exercise-stimulated glucose uptake in skeletal muscle. Ann Pediatr Endocrinol Metab 21:61-5