Important role for AMPKαl in limiting skeletal muscle cell hypertrophy

Mounier, Rémi; Lantier, Louise; Leclerc, Jocelyne; Sotiropoulos, Athanassia; Pende, Mario; Daegelen, Dominique; Sakamoto, Kei; Foretz, Marc; Viollet, Benoı̂t

doi:10.1096/fj.08-119057

Cited by 108 publications

(136 citation statements)

References 49 publications

(71 reference statements)

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“…Moreover, Paturi et al (55) suggested that impaired hypertrophy of slow-twitch skeletal muscle during overload in the diabetic rat was attributed partly to increased AMPK phosphorylation. A recent study using a knockout mouse model demonstrated that overload-induced muscle hypertrophy was accelerated in AMPK␣1-deficient mice compared with the wildtype mice (50). Correspondingly, we (13) showed in vitro that stimulation with a pharmacological AMPK agonist on cultured skeletal muscle cells inhibited myotube hypertrophy, and this response was attenuated in the AMPK␣1/␣2-knockdown condition.…”

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confidence: 76%

Involvement of AMPK in regulating slow-twitch muscle atrophy during hindlimb unloading in mice

Egawa

Goto

Ohno

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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-AMPK is considered to have a role in regulating skeletal muscle mass. However, there are no studies investigating the function of AMPK in modulating skeletal muscle mass during atrophic conditions. In the present study, we investigated the difference in unloading-associated muscle atrophy and molecular functions in response to 2-wk hindlimb suspension between transgenic mice overexpressing the dominant-negative mutant of AMPK (AMPK-DN) and their wild-type (WT) littermates. Male WT (n ϭ 24) and AMPK-DN (n ϭ 24) mice were randomly divided into two groups: an untreated preexperimental control group (n ϭ 12 in each group) and an unloading (n ϭ 12 in each group) group. The relative soleus muscle weight and fiber cross-sectional area to body weight were decreased by ϳ30% in WT mice by hindlimb unloading and by ϳ20% in AMPK-DN mice. There were no changes in puromycin-labeled protein or Akt/70-kDa ribosomal S6 kinase signaling, the indicators of protein synthesis. The expressions of ubiquitinated proteins and muscle RING finger 1 mRNA and protein, markers of the ubiquitin-proteasome system, were increased by hindlimb unloading in WT mice but not in AMPK-DN mice. The expressions of molecules related to the protein degradation system, phosphorylated forkhead box class O3a, inhibitor of B␣, microRNA (miR)-1, and miR-23a, were decreased only in WT mice in response to hindlimb unloading, and 72-kDa heat shock protein expression was higher in AMPK-DN mice than in WT mice. These results imply that AMPK partially regulates unloading-induced atrophy of slow-twitch muscle possibly through modulation of the protein degradation system, especially the ubiquitin-proteasome system. AMP-activated protein kinase; protein degradation; autophagy; ubiquitin-proteasome; microRNA; heat shock protein SKELETAL MUSCLE IS THE LARGEST TISSUE IN THE BODY, accounting for ϳ40% of the total body mass, and has a crucial role in metabolism as well as locomotion. Skeletal muscle has a high ability to adapt to multiple stimuli. Increased loading, such as resistance training and mechanical stretching, leads to skeletal muscle hypertrophy (18,75). In contrast, aging, poor nutrition, several diseases such as diabetes, cancer, sepsis, and chronic renal failure, and decreased loading, such as inactivity, lead to skeletal muscle atrophy (23,34,39). Skeletal muscle atrophy occurs as a result of changes in protein turnover: decreased protein synthesis, increased protein degradation, or a combination of both (17). The coordination of protein turnover in the atrophic process is regulated by complicated molecular responses, and the molecular mechanism involved in this process in skeletal muscle is not yet completely understood and remains to be elucidated.5=-AMP-activated protein kinase (AMPK) is well established as a metabolic sensor that helps maintain cellular energy homeostasis by modulating glucose, lipid, and protein metabolism (16,26,28). AMPK is a heterotrimeric kinase comprising a catalytic ␣-subunit and two regulatory subunits, the ␤-and ␥-subunits. Two ...

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confidence: 76%

Involvement of AMPK in regulating slow-twitch muscle atrophy during hindlimb unloading in mice

Egawa

Goto

Ohno

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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“…Previous reports revealed that overloading-induced muscle hypertrophy was accelerated in AMPK␣1 knockout mice (28) and that muscle mass and fiber cross-sectional area were greater in muscle-specific AMPK␣1/2-deficient mice than in transgenic control mice (22). Furthermore, in vitro studies demonstrated that AMPK negatively regulated the hypertrophy of muscle cells (22,28,30). Consistent with these observations, the levels of protein content and myotube diameter, indicators of hypertrophy, were less in AMPK-activated myotubes than in controls ( Figs.…”

Section: Discussionmentioning

confidence: 97%

“…Negative correlation between AMPK activity and the degree of hypertrophy in rat muscle have also been reported (35,39). These responses appear to be related to the deactivation of the signals in the protein synthesis pathway, mammalian target of rapamycin (mTOR)/p70 S6 kinase (p70 S6K ) (2,22,28), and to the activation of the signals in the protein degradation pathway, Forkhead box O transcription factors (Foxo) (31,36,41) and muscle-specific E3 ubiquitin ligases, such as muscle RING-finger 1 (MuRF1) and atrogin-1/muscle atrophy F-box (MAFbx) (19,30). Taken together, AMPK would act as a negative regulator for skeletal muscle mass through downregulation of protein synthesis and upregulation of protein degradation pathways.…”

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confidence: 85%

“…In addition, several studies in the past decade have suggested that AMPK plays an important role in the regulation of skeletal muscle mass. It has been reported that activation of AMPK inhibits myogenesis (9,27,41) and hypertrophy of skeletal muscle cells (22,28,30) and rodent skeletal muscle (22,28). Negative correlation between AMPK activity and the degree of hypertrophy in rat muscle have also been reported (35,39).…”

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confidence: 93%

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AICAR-induced activation of AMPK negatively regulates myotube hypertrophy through the HSP72-mediated pathway in C₂C₁₂skeletal muscle cells

Egawa

Ohno

Goto

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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induced activation of AMPK negatively regulates myotube hypertrophy through the HSP72-mediated pathway in C2C12 skeletal muscle cells. Am J Physiol Endocrinol Metab 306: E344 -E354, 2014. First published December 17, 2013; doi:10.1152/ajpendo.00495.2013.-5=-AMP-activated protein kinase (AMPK) plays an important role as a negative regulator of skeletal muscle mass. However, the precise mechanism of AMPK-mediated regulation of muscle mass is not fully clarified. Heat shock proteins (HSPs), stress-induced molecular chaperones, are related with skeletal muscle adaptation, but the association between AMPK and HSPs in skeletal muscle hypertrophy is unknown. Thus, we investigated whether AMPK regulates hypertrophy by mediating HSPs in C2C12 cells. The treatment with AICAR, a potent stimulator of AMPK, decreased 72-kDa HSP (HSP72) expression, whereas there were no changes in the expressions of 25-kDa HSP, 70-kDa heat shock cognate, and heat shock transcription factor 1 in myotubes. Protein content and diameter were less in the AICARtreated myotubes in those without treatment. AICAR-induced suppression of myotube hypertrophy and HSP72 expression was attenuated in the siRNA-mediated AMPK␣ knockdown myotubes. AICAR increased microRNA (miR)-1, a modulator of HSP72, and the increase of miR-1 was not induced in AMPK␣ knockdown condition. Furthermore, siRNA-mediated HSP72 knockdown blocked AICARinduced inhibition of myotube hypertrophy. AICAR upregulated the gene expression of muscle Ring-finger 1, and this alteration was suppressed in either AMPK␣ or HSP72 knockdown myotubes. The phosphorylation of p70 S6 kinase Thr 389 was downregulated by AICAR, whereas this was attenuated in AMPK␣, but not in HSP72, knockdown myotubes. These results suggest that AMPK inhibits hypertrophy through, in part, an HSP72-associated mechanism via miR-1 and protein degradation pathways in skeletal muscle cells. microRNA; heat shock transcription factor 1; muscle rRing-finger 1; atrogin-1; acetyl-CoA carboxylase SKELETAL MUSCLE HAS A GREATER CAPACITY to adapt to various stimuli. Increased loading, such as resistance training and mechanical stretching, stimulates protein synthesis and reduces protein degradation, thereby inducing muscle hypertrophy (10). On the other hand, decrease of use, such as immobilization, denervation, aging, and/or various pathological conditions, attenuates protein synthesis and increases protein degradation, resulting in atrophy (12,32). Although the process of skeletal muscle adaptation to hypertrophic and atrophic stimuli has been studied, the molecular mechanism involved in this process is not fully understood yet.5=-AMP-activated protein kinase (AMPK) is well known as a sensor for cellular energy status and metabolic stress, such as muscle contraction, fasting, hypoxia, ischemia, and/or oxidative and osmotic stresses and as a signaling intermediary that controls the use of glucose and fatty acids in skeletal muscle (8,14,15). In addition, several studies in the past decade have suggested that AMPK plays an important rol...

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“…The compensatory hypertrophy observed in this model involves activation of the Akt/mTOR signaling pathway (9,35). However, the effects of mechanical overload on markers of selected catabolic pathways, such as myostatin signaling or expression of the muscle-specific ubiquitin-ligases MAFbx and MURF1, remain controversial and have to be elucidated.…”

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confidence: 99%

Hypoxia transiently affects skeletal muscle hypertrophy in a functional overload model

Chaillou¹,

Koulmann²,

Simler³

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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-Hypoxia induces a loss of skeletal muscle mass, but the signaling pathways and molecular mechanisms involved remain poorly understood. We hypothesized that hypoxia could impair skeletal muscle hypertrophy induced by functional overload (Ov). To test this hypothesis, plantaris muscles were overloaded during 5, 12, and 56 days in female rats exposed to hypobaric hypoxia (5,500 m), and then, we examined the responses of specific signaling pathways involved in protein synthesis (Akt/mTOR) and breakdown (atrogenes). Hypoxia minimized the Ov-induced hypertrophy at days 5 and 12 but did not affect the hypertrophic response measured at day 56. Hypoxia early reduced the phosphorylation levels of mTOR and its downstream targets P70 S6K and rpS6, but it did not affect the phosphorylation levels of Akt and 4E-BP1, in Ov muscles. The role played by specific inhibitors of mTOR, such as AMPK and hypoxia-induced factors (i.e., REDD1 and BNIP-3) was studied. REDD1 protein levels were reduced by overload and were not affected by hypoxia in Ov muscles, whereas AMPK was not activated by hypoxia. Although hypoxia significantly increased BNIP-3 mRNA levels at day 5, protein levels remained unaffected. The mRNA levels of the two atrogenes MURF1 and MAFbx were early increased by hypoxia in Ov muscles. In conclusion, hypoxia induced a transient alteration of muscle growth in this hypertrophic model, at least partly due to a specific impairment of the mTOR/P70 S6K pathway, independently of Akt, by an undefined mechanism, and increased transcript levels for MURF1 and MAFbx that could contribute to stimulate the proteasomal proteolysis.

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Important role for AMPKαl in limiting skeletal muscle cell hypertrophy

Cited by 108 publications

References 49 publications

Involvement of AMPK in regulating slow-twitch muscle atrophy during hindlimb unloading in mice

Involvement of AMPK in regulating slow-twitch muscle atrophy during hindlimb unloading in mice

AICAR-induced activation of AMPK negatively regulates myotube hypertrophy through the HSP72-mediated pathway in C₂C₁₂skeletal muscle cells

Hypoxia transiently affects skeletal muscle hypertrophy in a functional overload model

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Important role for AMPKαl in limiting skeletal muscle cell hypertrophy

Cited by 108 publications

References 49 publications

Involvement of AMPK in regulating slow-twitch muscle atrophy during hindlimb unloading in mice

Involvement of AMPK in regulating slow-twitch muscle atrophy during hindlimb unloading in mice

AICAR-induced activation of AMPK negatively regulates myotube hypertrophy through the HSP72-mediated pathway in C2C12skeletal muscle cells

Hypoxia transiently affects skeletal muscle hypertrophy in a functional overload model

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AICAR-induced activation of AMPK negatively regulates myotube hypertrophy through the HSP72-mediated pathway in C₂C₁₂skeletal muscle cells