The role of AMP-activated protein kinase in the coordination of skeletal muscle turnover and energy homeostasis

Sanchez, Anthony M. J.; Candau, Robin; Csibi, Alfredo; Pagano, Allan; Raibon, Audrey; Bernardi, Henri

doi:10.1152/ajpcell.00125.2012

Cited by 101 publications

(93 citation statements)

References 131 publications

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“…AMPK plays a critical role in skeletal muscle metabolism by regulating a number of metabolic pathways in response to changes in cellular energy status (35,36). In addition to its effect on PGC1a-mediated mitochondrial biogenesis, AMPK stimulates lipid oxidation by inhibition of acetyl-CoA carboxylase-b (ACCb) (35).…”

Section: Discussionmentioning

confidence: 99%

Effect of testosterone on markers of mitochondrial oxidative phosphorylation and lipid metabolism in muscle of aging men with subnormal bioavailable testosterone

Petersson

Christensen

Kristensen

et al. 2014

European Journal of Endocrinology

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Objective: Recent studies have indicated that serum testosterone in aging men is associated with insulin sensitivity and expression of genes involved in oxidative phosphorylation (OxPhos), and that testosterone treatment increases lipid oxidation. Herein, we investigated the effect of testosterone therapy on regulators of mitochondrial biogenesis and markers of OxPhos and lipid metabolism in the skeletal muscle of aging men with subnormal bioavailable testosterone levels. Methods: Skeletal muscle biopsies were obtained before and after treatment with either testosterone gel (nZ12) or placebo (nZ13) for 6 months. Insulin sensitivity and substrate oxidation were assessed by euglycemic-hyperinsulinemic clamp and indirect calorimetry. Muscle mRNA levels and protein abundance and phosphorylation of enzymes involved in mitochondrial biogenesis, OxPhos, and lipid metabolism were examined by quantitative real-time PCR and western blotting. Results: Despite an increase in lipid oxidation (P!0.05), testosterone therapy had no effect on insulin sensitivity or mRNA levels of genes involved in mitochondrial biogenesis (PPARGC1A, PRKAA2, and PRKAG3), OxPhos (NDUFS1, ETFA, SDHA, UQCRC1, and COX5B), or lipid metabolism (ACADVL, CD36, CPT1B, HADH, and PDK4). Consistently, protein abundance of OxPhos subunits encoded by both nuclear (SDHA and UQCRC1) and mitochondrial DNA (ND6) and protein abundance and phosphorylation of AMP-activated protein kinase and p38 MAPK were unaffected by testosterone therapy. Conclusion: The beneficial effect of testosterone treatment on lipid oxidation is not explained by increased abundance or phosphorylation-dependent activity of enzymes known to regulate mitochondrial biogenesis or markers of OxPhos and lipid metabolism in the skeletal muscle of aging men with subnormal bioavailable testosterone levels.

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Section: Discussionmentioning

confidence: 99%

Effect of testosterone on markers of mitochondrial oxidative phosphorylation and lipid metabolism in muscle of aging men with subnormal bioavailable testosterone

Petersson

Christensen

Kristensen

et al. 2014

European Journal of Endocrinology

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“…AMP-activated protein kinase (AMPK) is an intracellular sensor of energy stress that can negatively regulate muscle protein synthesis in response to nutrient deficiency (54). AMPK can inhibit mTORC1 through the phosphorylation of tuberous sclerosis complex 2 and raptor, resulting in suppressed protein synthesis (22).…”

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confidence: 99%

Lewis lung carcinoma regulation of mechanical stretch-induced protein synthesis in cultured myotubes

Gao

Carson

2016

American Journal of Physiology-Cell Physiology

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“…Although energy sensors such as AMPK and mTORC are known to regulate cellular energy homeostasis and cell growth (9), there are indications that they could also modulate specific developmental processes. It was shown early that the mTORC inhibitor rapamycin inhibits growth of myofibers in regenerating adult muscle (10); such inhibition was overcome by expression of a rapamycin-resistant mTORC gene (11).…”

mentioning

confidence: 99%

Role of the mTORC1 Complex in Satellite Cell Activation by RNA-Induced Mitochondrial Restoration: Dual Control of Cyclin D1 through MicroRNAs

Jash

Dhar

Ghosh

et al. 2014

Molecular and Cellular Biology

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During myogenesis, satellite stem cells (SCs) are induced to proliferate and differentiate to myogenic precursors. The role of energy sensors such as the AMP-activated protein kinase (AMPK) and the mammalian Target of Rapamycin (mTOR) in SC activation is unclear. We previously observed that upregulation of ATP through RNA-mediated mitochondrial restoration (MR) accelerates SC activation following skeletal muscle injury. We show here that during regeneration, the AMPK-CRTC2-CREB and Raptor-mTORC-4EBP1 pathways were rapidly activated. The phosho-CRTC2-CREB complex was essential for myogenesis and activated transcription of the critical cell cycle regulator cyclin D1 (Ccnd1). Knockdown (KD) of either mTORC or its subunit Raptor delayed SC activation without influencing the differentiation program. KD of 4EBP1 had no effect on SC activation but enhanced myofiber size. mTORC1 positively regulated Ccnd1 translation but destabilized Ccnd1 mRNA. These antithetical effects of mTORC1 were mediated by two microRNAs (miRs) targeted to the 3= untranslated region (UTR) of Ccnd1 mRNA: miR-1 was downregulated in mTORC-KD muscle, and depletion of miR-1 resulted in increased levels of mRNA without any effect on Ccnd1 protein. In contrast, miR-26a was upregulated upon mTORC depletion, while anti-miR-26a oligonucleotide specifically stimulated Ccnd1 protein expression. Thus, mTORC may act as a timer of satellite cell proliferation during myogenesis. R egeneration of skeletal muscle following injury involves formation of new myofibers as well as patch repair of old injured fibers by fusion of satellite cell-derived myoblasts (1). The program of differentiation of satellite cells involves sequential expression of myogenic regulatory factors (MRFs) and their target genes (2-5). Mitochondrial biogenesis occurs at a specific time prior to the formation of myofibers (4, 6), suggesting an energy-requiring step, but the specific role of ATP in differentiation remains unknown. Eukaryotic cells contain a number of enzymes that sense the energy status, particularly, the pools of AMP and ADP (AMPactivated protein kinase [AMPK]) or of ATP (mammalian Target of Rapamycin [mTOR] kinases) (7,8). It is possible that mitochondrial activity, through modulation of the adenylate pool, impacts these energy sensors, thereby activating or inhibiting downstream pathways.Although energy sensors such as AMPK and mTORC are known to regulate cellular energy homeostasis and cell growth (9), there are indications that they could also modulate specific developmental processes. It was shown early that the mTORC inhibitor rapamycin inhibits growth of myofibers in regenerating adult muscle (10); such inhibition was overcome by expression of a rapamycin-resistant mTORC gene (11). Genetic ablation of mTORC (12), or of the mTORC1 subunit Raptor (13), or of the mTORC1 target S6K (14) results in severe muscle atrophy. These studies indicate that myofiber growth and maturation are regulated by mTORC1 acting through S6K in vivo but provide no information on the specific eff...

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The role of AMP-activated protein kinase in the coordination of skeletal muscle turnover and energy homeostasis

Cited by 101 publications

References 131 publications

Effect of testosterone on markers of mitochondrial oxidative phosphorylation and lipid metabolism in muscle of aging men with subnormal bioavailable testosterone

Effect of testosterone on markers of mitochondrial oxidative phosphorylation and lipid metabolism in muscle of aging men with subnormal bioavailable testosterone

Lewis lung carcinoma regulation of mechanical stretch-induced protein synthesis in cultured myotubes

Role of the mTORC1 Complex in Satellite Cell Activation by RNA-Induced Mitochondrial Restoration: Dual Control of Cyclin D1 through MicroRNAs

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