title: BRCA1 is a novel regulator of metabolic function in skeletal muscle.
abstract: Breast cancer type 1 (BRCA1) susceptibility protein is expressed across multiple tissues including skeletal muscle. The overall objective of this investigation was to define a functional role for BRCA1 in skeletal muscle using a translational approach. For the first time in both mice and humans, we identified the presence of multiple isoforms of BRCA1 in skeletal muscle. In response to an acute bout of exercise, we found increases in the interaction between the native forms of BRCA1 and the phosphorylated form of acetyl-CoA carboxylase. Decreasing BRCA1 content using a shRNA approach in cultured primary human myotubes resulted in decreased oxygen consumption by the mitochondria and increased reactive oxygen species production. The decreased BRCA1 content also resulted in increased storage of intracellular lipid and reduced insulin signaling. These results indicate that BRCA1 plays a critical role in the regulation of metabolic function in skeletal muscle. Collectively, these data reveal BRCA1 as a novel target to consider in our understanding of metabolic function and risk for development of metabolic-based diseases.
authors.affiliation: Department of Kinesiology, School of Public Health, University of Maryland, College Park, MD.
authors.forename: Kathryn C
authors.initials: KC
authors.lastname: Jackson
authors.forename: Eva-Karin
authors.initials: EK
authors.lastname: Gidlund
authors.forename: Jessica
authors.initials: J
authors.lastname: Norrbom
authors.forename: Ana P
authors.initials: AP
authors.lastname: Valencia
authors.forename: David M
authors.initials: DM
authors.lastname: Thomson
authors.forename: Rosemary A
authors.initials: RA
authors.lastname: Schuh
authors.forename: P Darrell
authors.initials: PD
authors.lastname: Neufer
authors.forename: Espen E
authors.initials: EE
authors.lastname: Spangenburg
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism; D000328:Adult; D000818:Animals; D019313:BRCA1 Protein / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000502:physiology; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D032448:Myoblasts, Skeletal / Q000378:metabolism; D010101:Oxygen Consumption; D010805:Physical Conditioning, Animal; D005082:Physical Exertion; D011499:Protein Processing, Post-Translational; D017382:Reactive Oxygen Species / Q000378:metabolism; D055815:Young Adult
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D007328:Insulin; D017382:Reactive Oxygen Species; D000263:Adenylate Kinase; C000588423:ACACA protein, human; D000103:Acetyl-CoA Carboxylase
keywords: breast cancer type 1; gene; insulin; lipid; mitochondria; muscle