The BRCA1 gene is well known for its role in cancer susceptibility in part due to its high susceptibility to missense mutations. The gene encodes a large protein that regulates multiple functions within the cell; however the majority of these functions have only been described in mammary tissue. What is generally under-appreciated is the fact that BRCA1 expression patterns extend beyond female reproductive tissue. For example, we have found that BRCA1 is expressed in skeletal muscle, but at this time BRCA1 has no defined role in skeletal muscle. Here our goal is to use an integrative approach to delineate the mechanisms BRCA1 regulate in skeletal muscle. Our preliminary data demonstrate that loss of BRCA1 function in skeletal muscle through use of an inducible genetic ablation approach results in muscle weakness, kyphosis, exercise intolerance, and reduced mitochondrial function. The first specific aim will seek to determine if BRCA1 expression is critical for skeletal muscle function. The second specific aim will seek to determine if BRCA1 expression is necessary for mitochondrial function in skeletal muscle. The third specific aim will seek to determine if known missense mutations in the BRCA1 gene contribute to reduced skeletal muscle function. In this proposal we will use state-of-the-art physiological and molecular approaches as a means to elucidate the physiological mechanisms BRCA1 regulates in skeletal muscle. Since BRCA1 presents with a significant amount of genetic variation, understanding the mechanisms that BRCA1 regulates in skeletal muscle have the potential to aid in the prevention of conditions such as sarcopenia, physical disability, etc.

Public Health Relevance

The breast and ovarian cancer susceptibility gene 1 (BRCA1) was identified in 1994 and is highly susceptible to heritable genetic mutations that lead to increased risk for cancer. BRCA1 is also found in skeletal muscle; however the functional role of BRCA1 in skeletal muscle remains unknown. Optimal skeletal muscle function is necessary for maintenance of overall functional independence, thus we will seek to determine the role of BRCA1 in skeletal muscle and the impact of two common genetic mutations in BRCA1 on skeletal muscle function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR066660-04
Application #
9531202
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Boyce, Amanda T
Project Start
2015-08-01
Project End
2020-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
East Carolina University
Department
Physiology
Type
Schools of Medicine
DUNS #
607579018
City
Greenville
State
NC
Country
United States
Zip Code
27858
Tarpey, Michael D; Amorese, Adam J; Balestrieri, Nicholas P et al. (2018) Characterization and utilization of the flexor digitorum brevis for assessing skeletal muscle function. Skelet Muscle 8:14
Ryan, Terence E; Yamaguchi, Dean J; Schmidt, Cameron A et al. (2018) Extensive skeletal muscle cell mitochondriopathy distinguishes critical limb ischemia patients from claudicants. JCI Insight 3:
O'Rourke, Allison R; Lindsay, Angus; Tarpey, Michael D et al. (2018) Impaired muscle relaxation and mitochondrial fission associated with genetic ablation of cytoplasmic actin isoforms. FEBS J 285:481-500
Schmidt, Cameron A; Amorese, Adam J; Ryan, Terence E et al. (2018) Strain-Dependent Variation in Acute Ischemic Muscle Injury. Am J Pathol 188:1246-1262
Jackson, Kathryn C; Tarpey, Michael D; Valencia, Ana P et al. (2018) Induced Cre-mediated knockdown of Brca1 in skeletal muscle reduces mitochondrial respiration and prevents glucose intolerance in adult mice on a high-fat diet. FASEB J 32:3070-3084
McClung, Joseph M; McCord, Timothy J; Ryan, Terence E et al. (2017) BAG3 (Bcl-2-Associated Athanogene-3) Coding Variant in Mice Determines Susceptibility to Ischemic Limb Muscle Myopathy by Directing Autophagy. Circulation 136:281-296
Schmidt, Cameron A; Ryan, Terence E; Lin, Chien-Te et al. (2017) Diminished force production and mitochondrial respiratory deficits are strain-dependent myopathies of subacute limb ischemia. J Vasc Surg 65:1504-1514.e11
Ryan, Terence E; Schmidt, Cameron A; Green, Thomas D et al. (2016) Targeted Expression of Catalase to Mitochondria Protects Against Ischemic Myopathy in High-Fat Diet-Fed Mice. Diabetes 65:2553-68