BRCA1 is a novel regulator of metabolic function in skeletal muscle

Abstract

This article is available online at http://www.jlr.org breast cancer and/or tumorigenesis in reproductive tissues ( 3 ). The BRCA1 gene produces either a full-length breast cancer type 1 susceptibility protein (BRCA1) or through alternatively splicing two documented variants, BRCA1 ⌬ 11 or BRCA1 ⌬ 11b, both of which lack a nuclear localization signal ( 4 ). Recently, BRCA1 was identifi ed as a regulator of lipid metabolism in human breast cancer cells (MCF7) as a result of direct interaction with the phosphorylated form of acetylCoA carboxylase (ACC-p) at the BRCA1 C-terminal (BRCT) domains ( 5, 6 ). The interaction encourages the maintenance of the phosphorylated state of ACC thereby altering lipid metabolism in the cancer cell line ( 5, 6 ).ACC has two isoforms, ACC1 or ACC2, with ACC2 containing an extra 146 amino acids in the NH 2 -terminal region. ACC activity is negatively regulated by phosphorylation of residue Ser 79 on ACC1 and Ser 221 on ACC2 ( 7,8 ). In the active form (i.e., dephosphorylated), ACC catalyzes the carboxylation of acetyl-CoA into malonyl-CoA (MaCoA). Changes in cellular MaCoA content alter intracellular lipid dynamics in two specifi c manners ( 9, 10 ). MaCoA directly contributes to de novo synthesis of palmitate via FAS and MaCoA also allosterically inhibits carnitine palmitoyltransferase-1 (CPT-1), a mitochondrial long chain fatty acid transporter ( 11 ). Thus, in mammary tissue the ability of BRCA1 to affect ACC activity alters cellular lipid concentrations by indirectly regulating rates of fatty acid synthesis and/or the fl ux of fatty acids into the mitochondria.Abstract Breast cancer type 1 (BRCA1) susceptibility protein is expressed across multiple tissues including skeletal muscle. The overall objective of this investigation was to defi ne a functional role for BRCA1 in skeletal muscle using a translational approach. For the fi rst time in both mice and humans, we identifi ed 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. -Jackson, K. C., E-K. Gidlund, J. Abbreviations: ACC, acetyl-CoA carboxylase; ACC-p, phosphorylated form of acetyl-CoA carboxylase; AICAR, 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide; AMPK, AMP-activated protein kinase; BRCA1, Breast Cancer 1, early onset; BRCA1 MG KO, mammary gland tissue fr...

Uninterrupted Sedentary Behavior Downregulates BRCA1 Gene Expression

“…A similar energy balance mechanism may link prolonged sedentary bouts with reduced BRCA1 expression. BRCA1 is a key regulator of metabolism; by binding to the inactive form of Acetyl-CoA Carboxylase (ACCA), BRCA1 reduces the rate of long-chain fatty acid synthesis (51,52). Thus, lipoprotein lipase and BRCA1 play complementary roles in response to increased energy needs: lipoprotein lipase breaks down fats and BRCA1 reduces their synthesis.…”

Induced Cre‐mediated knockdown of Brca1 in skeletal muscle reduces mitochondrial respiration and prevents glucose intolerance in adult mice on a high‐fat diet

“…We recently demonstrated that Brca1 is expressed in skeletal muscle and is a critical regulator of metabolic function in cultured human myotubes (5). Specifically, we found that in vitro knockdown of Brca1 expression resulted in reduced mitochondrial O 2 consumption in these cells (5).…”

“…We recently demonstrated that Brca1 is expressed in skeletal muscle and is a critical regulator of metabolic function in cultured human myotubes (5). Specifically, we found that in vitro knockdown of Brca1 expression resulted in reduced mitochondrial O 2 consumption in these cells (5). Others have shown that overexpression of Brca1 in cultured MCF7 cells, a breast cancer cell line, increased oxidative gene expression, whereas loss of Brca1 expression increased glycolytic gene expression (6).…”

Loss of BRCA1 in the Cells of Origin of Ovarian Cancer Induces Glycolysis: A Window of Opportunity for Ovarian Cancer Chemoprevention

“…In fact, little is known about BRCA1’s role in metabolism in normal tissue. In cardiomyocytes, loss of BRCA1 has been reported to reduce glucose levels and fatty acid oxidation (36) and in skeletal muscle, BRCA1 loss reduces fatty acid synthesis (37). Menendez and colleagues use targeted metabolomics to show that breast epithelial cells transfected with a BRCA1 mutation (185delAG) undergo metabolic reprograming to increase anabolic processes, including the tricarboxylic acid (TCA) cycle and lipogenesis (38).…”