AMPK controls exercise endurance, mitochondrial oxidative capacity, and skeletal muscle integrity

Louise Lantier; Joachim Fentz; Rémi Mounier; Jocelyne Leclerc; Jonas Thue Treebak; Christian Kirkegaard Pehmøller; Nieves Sanz; Iori Sakakibara; Emmanuelle Saint-Amand; Stéphanie Rimbaud; Pascal Maire; André Marette; Renée Ventura-Clapier; Arnaud Ferry; Jørgen Wojtaszewski; Marc Foretz; Benoit Viollet

doi:10.1096/fj.14-250449

AMPK controls exercise endurance, mitochondrial oxidative capacity, and skeletal muscle integrity

Louise Lantier, Joachim Fentz, Rémi Mounier, Jocelyne Leclerc, Jonas Thue Treebak, Christian Kirkegaard Pehmøller, Nieves Sanz, Iori Sakakibara, Emmanuelle Saint-Amand, Stéphanie Rimbaud, Pascal Maire, André Marette, Renée Ventura-Clapier, Arnaud Ferry, Jørgen Wojtaszewski, Marc Foretz, Benoit Viollet

August Krogh Sektionen for Molekylær Fysiologi

122 Citationer (Scopus)

Abstract

AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that plays a central role in skeletal muscle metabolism. We used skeletal muscle-specific AMPKα1α2 double-knockout (mdKO) mice to provide direct genetic evidence of the physiological importance of AMPK in regulating muscle exercise capacity, mitochondrial function, and contraction-stimulated glucose uptake. Exercise performance was significantly reduced in the mdKO mice, with a reduction in maximal force production and fatigue resistance. An increase in the proportion of myofibers with centralized nuclei was noted, as well as an elevated expression of interleukin 6 (IL-6) mRNA, possibly consistent with mild skeletal muscle injury. Notably, we found that AMPKα1 and AMPKα2 isoforms are dispensable for contraction-induced skeletal muscle glucose transport, except for male soleus muscle. However, the lack of skeletal muscle AMPK diminished maximal ADP-stimulated mitochondrial respiration, showing an impairment at complex I. This effect was not accompanied by changes in mitochondrial number, indicating that AMPK regulates muscle metabolic adaptation through the regulation of muscle mitochondrial oxidative capacity and mitochondrial substrate utilization but not baseline mitochondrial muscle content. Together, these results demonstrate that skeletal muscle AMPK has an unexpected role in the regulation of mitochondrial oxidative phosphorylation that contributes to the energy demands of the exercising muscle.

Originalsprog	Engelsk
Tidsskrift	F A S E B Journal
Vol/bind	28
Udgave nummer	7
Sider (fra-til)	3211-3224
Antal sider	14
ISSN	0892-6638
DOI	https://doi.org/10.1096/fj.14-250449
Status	Udgivet - 1 jul. 2014

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10.1096/fj.14-250449

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Lantier, L., Fentz, J., Mounier, R., Leclerc, J., Treebak, J. T., Pehmøller, C. K., Sanz, N., Sakakibara, I., Saint-Amand, E., Rimbaud, S., Maire, P., Marette, A., Ventura-Clapier, R., Ferry, A., Wojtaszewski, J., Foretz, M., & Viollet, B. (2014). AMPK controls exercise endurance, mitochondrial oxidative capacity, and skeletal muscle integrity. F A S E B Journal, 28(7), 3211-3224. https://doi.org/10.1096/fj.14-250449

Lantier, L, Fentz, J, Mounier, R, Leclerc, J, Treebak, JT, Pehmøller, CK, Sanz, N, Sakakibara, I, Saint-Amand, E, Rimbaud, S, Maire, P, Marette, A, Ventura-Clapier, R, Ferry, A, Wojtaszewski, J, Foretz, M & Viollet, B 2014, 'AMPK controls exercise endurance, mitochondrial oxidative capacity, and skeletal muscle integrity', F A S E B Journal, bind 28, nr. 7, s. 3211-3224. https://doi.org/10.1096/fj.14-250449

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title = "AMPK controls exercise endurance, mitochondrial oxidative capacity, and skeletal muscle integrity",

abstract = "AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that plays a central role in skeletal muscle metabolism. We used skeletal muscle-specific AMPKα1α2 double-knockout (mdKO) mice to provide direct genetic evidence of the physiological importance of AMPK in regulating muscle exercise capacity, mitochondrial function, and contraction-stimulated glucose uptake. Exercise performance was significantly reduced in the mdKO mice, with a reduction in maximal force production and fatigue resistance. An increase in the proportion of myofibers with centralized nuclei was noted, as well as an elevated expression of interleukin 6 (IL-6) mRNA, possibly consistent with mild skeletal muscle injury. Notably, we found that AMPKα1 and AMPKα2 isoforms are dispensable for contraction-induced skeletal muscle glucose transport, except for male soleus muscle. However, the lack of skeletal muscle AMPK diminished maximal ADP-stimulated mitochondrial respiration, showing an impairment at complex I. This effect was not accompanied by changes in mitochondrial number, indicating that AMPK regulates muscle metabolic adaptation through the regulation of muscle mitochondrial oxidative capacity and mitochondrial substrate utilization but not baseline mitochondrial muscle content. Together, these results demonstrate that skeletal muscle AMPK has an unexpected role in the regulation of mitochondrial oxidative phosphorylation that contributes to the energy demands of the exercising muscle.",

author = "Louise Lantier and Joachim Fentz and R{\'e}mi Mounier and Jocelyne Leclerc and Treebak, {Jonas Thue} and Pehm{\o}ller, {Christian Kirkegaard} and Nieves Sanz and Iori Sakakibara and Emmanuelle Saint-Amand and St{\'e}phanie Rimbaud and Pascal Maire and Andr{\'e} Marette and Ren{\'e}e Ventura-Clapier and Arnaud Ferry and J{\o}rgen Wojtaszewski and Marc Foretz and Benoit Viollet",

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T1 - AMPK controls exercise endurance, mitochondrial oxidative capacity, and skeletal muscle integrity

AU - Lantier, Louise

AU - Fentz, Joachim

AU - Mounier, Rémi

AU - Leclerc, Jocelyne

AU - Treebak, Jonas Thue

AU - Pehmøller, Christian Kirkegaard

AU - Sanz, Nieves

AU - Sakakibara, Iori

AU - Saint-Amand, Emmanuelle

AU - Rimbaud, Stéphanie

AU - Maire, Pascal

AU - Marette, André

AU - Ventura-Clapier, Renée

AU - Ferry, Arnaud

AU - Wojtaszewski, Jørgen

AU - Foretz, Marc

AU - Viollet, Benoit

N1 - CURIS 2014 NEXS 089

PY - 2014/7/1

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N2 - AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that plays a central role in skeletal muscle metabolism. We used skeletal muscle-specific AMPKα1α2 double-knockout (mdKO) mice to provide direct genetic evidence of the physiological importance of AMPK in regulating muscle exercise capacity, mitochondrial function, and contraction-stimulated glucose uptake. Exercise performance was significantly reduced in the mdKO mice, with a reduction in maximal force production and fatigue resistance. An increase in the proportion of myofibers with centralized nuclei was noted, as well as an elevated expression of interleukin 6 (IL-6) mRNA, possibly consistent with mild skeletal muscle injury. Notably, we found that AMPKα1 and AMPKα2 isoforms are dispensable for contraction-induced skeletal muscle glucose transport, except for male soleus muscle. However, the lack of skeletal muscle AMPK diminished maximal ADP-stimulated mitochondrial respiration, showing an impairment at complex I. This effect was not accompanied by changes in mitochondrial number, indicating that AMPK regulates muscle metabolic adaptation through the regulation of muscle mitochondrial oxidative capacity and mitochondrial substrate utilization but not baseline mitochondrial muscle content. Together, these results demonstrate that skeletal muscle AMPK has an unexpected role in the regulation of mitochondrial oxidative phosphorylation that contributes to the energy demands of the exercising muscle.

AB - AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that plays a central role in skeletal muscle metabolism. We used skeletal muscle-specific AMPKα1α2 double-knockout (mdKO) mice to provide direct genetic evidence of the physiological importance of AMPK in regulating muscle exercise capacity, mitochondrial function, and contraction-stimulated glucose uptake. Exercise performance was significantly reduced in the mdKO mice, with a reduction in maximal force production and fatigue resistance. An increase in the proportion of myofibers with centralized nuclei was noted, as well as an elevated expression of interleukin 6 (IL-6) mRNA, possibly consistent with mild skeletal muscle injury. Notably, we found that AMPKα1 and AMPKα2 isoforms are dispensable for contraction-induced skeletal muscle glucose transport, except for male soleus muscle. However, the lack of skeletal muscle AMPK diminished maximal ADP-stimulated mitochondrial respiration, showing an impairment at complex I. This effect was not accompanied by changes in mitochondrial number, indicating that AMPK regulates muscle metabolic adaptation through the regulation of muscle mitochondrial oxidative capacity and mitochondrial substrate utilization but not baseline mitochondrial muscle content. Together, these results demonstrate that skeletal muscle AMPK has an unexpected role in the regulation of mitochondrial oxidative phosphorylation that contributes to the energy demands of the exercising muscle.

U2 - 10.1096/fj.14-250449

DO - 10.1096/fj.14-250449

M3 - Journal article

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SN - 0892-6638

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SP - 3211

EP - 3224

JO - F A S E B Journal

JF - F A S E B Journal

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ER -

AMPK controls exercise endurance, mitochondrial oxidative capacity, and skeletal muscle integrity

Abstract

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