Skeletal Muscle AMP-activated Protein Kinase Is Essential for the Metabolic Response to Exercise in Vivo

Lee-Young, Robert S.; Griffee, Susan R.; Lynes, Sara E.; Bracy, Deanna P.; Ayala, Julio E.; McGuinness, Owen P.; Wasserman, David H.

doi:10.1074/jbc.m109.021048

Cited by 145Metabolism, Diabetes, and CancerCardiovascular and exercise physiologyAdipose Tissue and Metabolism

Skeletal Muscle AMP-activated Protein Kinase Is Essential for the Metabolic Response to Exercise in Vivo

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Lee-Young, Robert S., Griffee, Susan R., Lynes, Sara E., Bracy, Deanna P., Ayala, Julio E., McGuinness, Owen P., Wasserman, David H.·2009·Journal of Biological Chemistry

DOI 10.1074/jbc.m109.021048PMC PMC2781986

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Abstract

AMP-activated protein kinase (AMPK) has been postulated as a super-metabolic regulator, thought to exert numerous effects on skeletal muscle function, metabolism, and enzymatic signaling. Despite these assertions, little is known regarding the direct role(s) of AMPK in vivo, and results obtained in vitro or in situ are conflicting. Using a chronically catheterized mouse model (carotid artery and jugular vein), we show that AMPK regulates skeletal muscle metabolism in vivo at several levels, with the result that a deficit in AMPK activity markedly impairs exercise tolerance. Compared with wild-type littermates at the same relative exercise capacity, vascular glucose delivery and skeletal muscle glucose uptake were impaired; skeletal muscle ATP degradation was accelerated, and arterial lactate concentrations were increased in mice expressing a kinase-dead AMPKalpha2 subunit (alpha2-KD) in skeletal muscle. Nitric-oxide synthase (NOS) activity was significantly impaired at rest and in response to exercise in alpha2-KD mice; expression of neuronal NOS (NOSmicro) was also reduced. Moreover, complex I and IV activities of the electron transport chain were impaired 32 +/- 8 and 50 +/- 7%, respectively, in skeletal muscle of alpha2-KD mice (p < 0.05 versus wild type), indicative of impaired mitochondrial function. Thus, AMPK regulates neuronal NOSmicro expression, NOS activity, and mitochondrial function in skeletal muscle. In addition, these results clarify the role of AMPK in the control of muscle glucose uptake during exercise. Collectively, these findings demonstrate that AMPK is central to substrate metabolism in vivo, which has important implications for exercise tolerance in health and certain disease states characterized by impaired AMPK activation in skeletal muscle.

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AMPK α2 KO and α2 KD and α2iTg mice have normal or only modest reductions in glucose uptake during contractions.
“AMPK α2 KO and α2 KD and α2iTg mice have normal or only modest reductions in glucose uptake during contractions [4,26,31,32,118-120].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [118]

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Authors: Lee-Young, R. S., Griffee, S. R., Lynes, S. E., Bracy, D. P., Ayala, J. E., McGuinness, O. P., & Wasserman, D. H.
Affiliations: Vanderbilt University (US)
ORCID: Ayala, Julio E.
McGuinness, Owen P.
Wasserman, David H.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2009-09
Volume: 284
Issue: 36
Pages: 23925-23934
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m109.021048
PMC: PMC2781986
OpenAlex: W2034465871
Cited by: 145
References: 55
Citations by year: 2026: 5 · 2025: 4 · 2024: 3 · 2023: 5 · 2022: 8 · 2021: 7 · 2020: 6 · 2019: 5 · 2018: 2 · 2017: 7 · 2016: 13 · 2015: 13 · 2014: 14 · 2013: 14 · 2012: 13
FWCI: 5.24
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 4063 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Diabetes and Digestive and Kidney Diseases (U24DK59637, U24DK059637, R01 DK 54902, R01DK054902)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Keywords: AMPK, skeletal muscle metabolism, exercise tolerance, muscle glucose uptake, nitric oxide synthase, neuronal nitric oxide synthase, mitochondrial function, electron transport chain, ATP degradation, lactate, substrate metabolism
MeSH terms: Animals, Enzyme Activation, Female, Glucose, Male, Mice, Transgenic, Physical Conditioning, Animal, Physical Endurance, Muscle, Skeletal, Mice, Nitric Oxide Synthase Type I, AMP-Activated Protein Kinases

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Skeletal Muscle AMP-activated Protein Kinase Is Essential for the Metabolic Response to Exercise in Vivo

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