Ectopic lipid deposition and the metabolic profile of skeletal muscle in ovariectomized mice

Jackson, Kathryn C.; Wohlers, Lindsay M.; Lovering, Richard M.; Schuh, Rosemary A.; Maher, Amy C.; Bonen, Arend; Koves, Timothy R.; Thomson, David M.; Muoio, Deborah M.; Spangenburg, Espen E.

doi:10.1152/ajpregu.00428.2012

Cited by 31 publications

(36 citation statements)

References 70 publications

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“…In a study that compared the effects of OVX in mice and rats 40 , the latter gain more weight than sham-operated animals, but primarily through increases in the parametrial and mesenteric (i.e., intra-abdominal) fat pads, suggesting the possibility of species differences in regional fat expansion. However, this species difference has not been a consistent finding, as the expansion of subcutaneous, but not intra-abdominal, fat has been observed in OVX rats 41 , and the expansion of intra-abdominal fat has been observed in OVX mice 42, 43 . Most evidence indicates that OVX results in excess fat accumulation in laboratory animals, with a disproportionate amount stored in abdominal regions.…”

Section: Pre-clinical Researchmentioning

confidence: 89%

Regulation of Body Composition and Bioenergetics by Estrogens

Pelt

Gavin

Kohrt

2015

Endocrinology and Metabolism Clinics of North America

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SYNOPSIS Evidence from basic, preclinical, and clinical research points to an important role of estradiol (E2) in the regulation of body composition and bioenergetics. There is consistent evidence from basic and preclinical research that the disruption of E2 signaling, through either genetic manipulation (e.g., estrogen receptor deletion) or surgical intervention (e.g., ovariectomy), accelerates fat accumulation, with a disproportionate increase in abdominal fat. Clinical evidence for the regulation of body composition and bioenergetics by E2 is less consistent. Evidence exists both for and against menopause as the mediator of changes in body composition. This is likely related to the prolonged nature of the menopause transition in women and the associated complexities of distinguishing effects of the loss of gonadal function from other phenomena of aging. However, a need remains to better understand the metabolic actions of estrogens in women because of the potential impact on health after the menopause.

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Section: Pre-clinical Researchmentioning

confidence: 89%

Regulation of Body Composition and Bioenergetics by Estrogens

Pelt

Gavin

Kohrt

2015

Endocrinology and Metabolism Clinics of North America

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“…Human skeletal muscle biopsies were homogenized on ice using glass-on-glass homogenizers in RIPA buffer [150 mM NaCl, 10 mM Tris-HCl, 5 mM EDTA, 0.5% Na deoxycholate, 0.1% SDS, 1% Triton X-100, and protein inhibitor cocktail complete mini (Roche Diagnostics)]. Total protein was determined in each sample using the Pierce BCA protein assay (mouse) or Bradford protein assay (human) as previously described ( 20,21 ).…”

Section: Homogenizationmentioning

confidence: 99%

“…Immunoblotting for either BRCA1 immunoprecipitation solution or whole muscle homogenate protein was performed as previously described ( 15,20,22 ). Membranes were probed with an antibody specifi c for BRCA1 (I-20 or D-20, 1:200; Santa Cruz Biotechnology), ACC-p or ACC total (1:1,000; Cell Signal, Boston, MA), Akt-p or Akt total (1:1,000; Cell Signal), ␣ -actinin (1:5,000; Sigma-Aldrich, Saint Louis, MO), red fl uorescent protein (RFP) (1:2,000; Thermo Scientifi c, Waltham, MA).…”

Section: Immunoblotting Analysismentioning

confidence: 99%

“…MaCoA measures were performed on the gastrocnemius muscles from sedentary and acute exercise female and male mice as previously described ( 20 ).…”

Section: Mouse Macoa Measuresmentioning

confidence: 99%

“…Mitochondrial oxygen consumption rates (OCRs) were measured in shRNA-hBRCA1-or scrambled-shRNA-treated human myotubes similar to our previously described technique ( 20,30 ). In parallel plates, ACC phosphorylation was assessed after 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) treatment in the same myotubes with either normal or reduced BRCA1 content.…”

Section: Mitochondrial Oxygen Consumptionmentioning

confidence: 99%

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BRCA1 is a novel regulator of metabolic function in skeletal muscle

Jackson

Gidlund

Norrbom

et al. 2014

Journal of Lipid Research

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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...

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Acute rimonabant treatment promotes protein synthesis in C2C12 myotubes through a CB1‐independent mechanism

Bacquer

Lanchais

Combe

et al. 2020

Journal Cellular Physiology

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Sarcopenia is an age‐related loss of muscle mass associated with changes in skeletal muscle protein homeostasis due to lipid accumulation and anabolic resistance; changes that are also commonly described in obesity. Activation of the endocannabinoid system is associated with the development of obesity and insulin resistance, and with the perturbed skeletal muscle development. Taken together this suggests that endocannabinoids could be regulators of skeletal muscle protein homeostasis. Here we report that rimonabant, an antagonist for the CB1 receptor, can prevent dexamethasone‐induced C2C12 myotube atrophy without affecting the mRNA expression of atrogin‐1/MAFbx (a marker of proteolysis), which suggests it is involved in the control of protein synthesis. Rimonabant alone stimulates protein synthesis in a time‐ and dose‐dependent manner through mTOR‐ and intracellular calcium‐dependent mechanisms. CB1 agonists are unable to modulate protein synthesis or prevent the effect of rimonabant. Using C2C12 cells stably expressing an shRNA directed against CB1, or HEK293 cells overexpressing HA‐tagged CB1, we demonstrated that the effect of rimonabant is unaffected by CB1 expression level. In summary, rimonabant can stimulate protein synthesis in C2C12 myotubes through a CB1‐independent mechanism. These results highlight the need to identify non‐CB1 receptor(s) mediating the pro‐anabolic effect of rimonabant as potential targets for the treatment of sarcopenia, and to design new side‐effect‐free molecules that consolidate the effect of rimonabant on skeletal muscle protein synthesis.

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Ectopic lipid deposition and the metabolic profile of skeletal muscle in ovariectomized mice

Cited by 31 publications

References 70 publications

Regulation of Body Composition and Bioenergetics by Estrogens

Regulation of Body Composition and Bioenergetics by Estrogens

BRCA1 is a novel regulator of metabolic function in skeletal muscle

Acute rimonabant treatment promotes protein synthesis in C2C12 myotubes through a CB1‐independent mechanism

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