Changes in contraction‐induced phosphorylation of AMP‐activated protein kinase and mitogen‐activated protein kinases in skeletal muscle after ovariectomy

Wohlers, Lindsay M.; Sweeney, Sean M.; Ward, Christopher W.; Lovering, Richard M.; Spangenburg, Espen E.

doi:10.1002/jcb.22113

Cited by 27 publications

(24 citation statements)

References 47 publications

(50 reference statements)

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“…Importantly, when such shifts are detected they are modest, in the magnitude of 10% or less, and thus likely have little impact on the extent of force potentiation reported here. E 2 activates several kinases and signaling pathways in various skeletal muscle cell lines (4,8,48) and skeletal muscle of rodents (32,56,68). In our screen of E 2 -responsive kinases using a kinase inhibitor library and C 2 C 12 cells, we identified 11 inhibitors that decreased pRLC triggered by E 2 ( Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…For example, ERs have been implicated in the regulation of gene transcription in myoblasts, including kinases that regulate GLUT4, myogenin, and myosin heavy chain expression (12). E 2 is also an important molecule activating several kinases and kinase cascades, such as phosphatidylinositide 3-kinase/Akt (PI3K/Akt), MAPK, and AMP-activated protein kinase (AMPK), in a multitude of cells and tissues including skeletal muscle (46,48,68). These cellular processes result in altered kinase activity and thus protein phosphorylation.…”

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confidence: 99%

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Estradiol modulates myosin regulatory light chain phosphorylation and contractility in skeletal muscle of female mice

Lai

Collins

Colson

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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-Impairment of skeletal muscle function has been associated with changes in ovarian hormones, especially estradiol. To elucidate mechanisms of estradiol on skeletal muscle strength, the hormone's effects on phosphorylation of the myosin regulatory light chain (pRLC) and muscle contractility were investigated, hypothesizing an estradiol-specific beneficial impact. In a skeletal muscle cell line, C 2C12, pRLC was increased by 17␤-estradiol (E 2) in a concentration-dependent manner. In skeletal muscles of C57BL/6 mice that were E 2 deficient via ovariectomy (OVX), pRLC was lower than that from ovary-intact, sham-operated mice (Sham). The reduced pRLC in OVX muscle was reversed by in vivo E 2 treatment. Posttetanic potentiation (PTP) of muscle from OVX mice was low compared with that from Sham mice, and this decrement was reversed by acute E 2 treatment, demonstrating physiological consequence. Western blot of those muscles revealed that low PTP corresponded with low pRLC and higher PTP with greater pRLC. We aimed to elucidate signaling pathways affecting E 2-mediated pRLC using a kinase inhibitor library and C 2C12 cells as well as a specific myosin light chain kinase inhibitor in muscles. PI3K/Akt, MAPK, and CamKII were identified as candidate kinases sensitive to E 2 in terms of phosphorylating RLC. Applying siRNA strategy in C 2C12 cells, pRLC triggered by E 2 was found to be mediated by estrogen receptor-␤ and the G protein-coupled estrogen receptor. Together, these results provide evidence that E 2 modulates myosin pRLC in skeletal muscle and is one mechanism by which this hormone can affect muscle contractility in females. estrogen; estrogen receptor; kinase; post tetanic potentiation; RLC OVARIAN HORMONE DEFICIENCY is related to muscle dysfunction and loss of strength. For example, declines in strength are accelerated around the time of menopause (35,41,51), and skeletal muscles of postmenopausal women on estrogen-based hormone therapy are stronger than those not on hormone therapy (10,17,49). In mouse models, contractile characteristics are impaired in muscles of ovariectomized compared with sham-operated mice (16,38,39,53,65). It was suggested (41) and subsequently demonstrated that ovarian hormones influence muscle strength by directly affecting the function of contractile proteins (43,66), particularly the structure and function of myosin (38,39). Among the ovarian hormones, 17␤-estradiol (E 2 ) appears to be the key hormone, because it reverses muscle weakness and contractile protein dysfunction caused by ovariectomy. Specifically, reduced muscle and contractile protein functions were restored when E 2 was administered to ovariectomized mice (16,38,53). In a chemical model of premature aging, of which the ovaries of young adult mice were locally and specifically induced to be senescent, E 2 treatment improved some muscle contractile functions (18). Although these studies have demonstrated that E 2 impacts muscle and myosin functions, the molecular mechanisms by which this hormone affects the structure a...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Estradiol modulates myosin regulatory light chain phosphorylation and contractility in skeletal muscle of female mice

Lai

Collins

Colson

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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“…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%

“…The mean (range) age, height, and weight were 26 (21)(22)(23)(24)(25)(26)(27)(28)(29)(30) years, 177 (158-190) cm, and 75 (58-90) kg, respectively. The mean (range) maximal oxygen consumption (VO 2 max) was 48 ml·kg Ϫ 1 ·min Ϫ 1 .…”

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confidence: 99%

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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“…Protein concentrations were determined on the supernatant using the BCA protein assay. Equal amounts of total protein (75 mg) were resolved on 10% SDS-PAGE gels and transferred to PVDF membranes as previously described [Spangenburg et al, 2008;Wohlers et al, 2009]. Blots were visualized with Ponceau S (Sigma Chemical) to confirm equal loading of the lanes and then blocked with 5% nonfat dry milk in Tris-buffered saline with 0.1% Tween (TBS-T).…”

Section: Western Blotting Of Adipose Tissuementioning

confidence: 99%

17β‐estradiol supplementation attenuates ovariectomy‐induced increases in ATGL signaling and reduced perilipin expression in visceral adipose tissue

Wohlers

Spangenburg

2010

J of Cellular Biochemistry

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Adipocytes from post-menopausal females have higher basal lipolytic rates than pre-menopausal females, which contributes to increased risk of developing dyslipidemia following menopause. The purpose of this study was to delineate cellular mechanisms affecting adipose tissue function in the ovariectomized (OVX) mouse and also determine if physical activity or estrogen supplementation alter any detected changes. Female C57/Bl6 mice were placed into SHAM, OVX sedentary (OVX), OVX exercise (OVX-Ex), and OVX sedentary + 17beta-estradiol (OVX + E(2)) groups. Visceral fat mass, glycerol, and NEFA levels were significantly higher in OVX mice compared to SHAM animals, but were not elevated in the E(2)-treated animals. Voluntary running failed to change circulating levels of glycerol or NEFA in OVX mice, but did partially attenuate the increase in visceral fat mass. Adipose triglyceride lipase (ATGL) protein content was significantly elevated in visceral fat from OVX and OVX-Ex groups compared to SHAM, while ATGL-CGI-58 interaction was significantly higher in OVX than SHAM and OVX + E(2) mice. No significant differences in HSL phosphorylation were detected between groups, however, ERK1/2 phosphorylation was significantly elevated in the OVX mice. To determine if ERK1/2 function was critical for the increased glycerol levels, visceral fat was treated with MEK inhibitor PD98059, with no differences in glycerol release detected. Perilipin protein content was decreased significantly in OVX and OVX-Ex mice compared to SHAM. Thus, these data suggest that increased ATGL signaling and reduced perilipin protein content may contribute to increased NEFA and glycerol levels in OVX mice, which are attenuated with E(2) treatment, but not by exercise.

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Changes in contraction‐induced phosphorylation of AMP‐activated protein kinase and mitogen‐activated protein kinases in skeletal muscle after ovariectomy

Cited by 27 publications

References 47 publications

Estradiol modulates myosin regulatory light chain phosphorylation and contractility in skeletal muscle of female mice

Estradiol modulates myosin regulatory light chain phosphorylation and contractility in skeletal muscle of female mice

BRCA1 is a novel regulator of metabolic function in skeletal muscle

17β‐estradiol supplementation attenuates ovariectomy‐induced increases in ATGL signaling and reduced perilipin expression in visceral adipose tissue

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