Research Articles
BRCA1 is a novel regulator of metabolic function in skeletal muscle

https://doi.org/10.1194/jlr.M043851Get rights and content
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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.

breast cancer type 1
muscle
gene
mitochondria
lipid
insulin

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This work was funded by National Institutes of Health Grant AR059913 (E.E.S.), an ACSM student doctoral grant (K.C.J.), and a KNES GRIF fund grant (K.C.J.). K.C.J. was supported by National Institutes of Health Grant AG000268. J.N. was supported by the Swedish National Centre for Research in Sports. R.A.S. was supported by VA Research Service Rehabilitation R&D REAP and Biomedical R&D CDA02.

Abbreviations:

    ACC

    acetyl-CoA carboxylase

    ACC-p

    phosphorylated form of acetyl-CoA carboxylase

    AICAR

    5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide

    AMPK

    AMP-activated protein kinase

    BRCA1

    Breast Cancer 1, early onset

    BRCA1 MG KO

    mammary gland tissue from breast cancer type 1 KO mice

    BRCT

    after the C_terminal domain of a breast cancer susceptibility protein

    CPT-1

    carnitine palmitoyltransferase-1

    DCF

    2′,7′-dich­lorofluorescein

    HFD

    high-fat diet

    MaCoA

    malonyl-CoA

    2-NBDG

    2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucoseR

    NCD

    normal chow diet

    OCR

    oxygen consumption rate

    RFP

    red fluorescent protein

    ROS

    reactive oxygen species

    TA

    tibialis anterior

    VL

    vastus lateralis