Loss of Skeletal Muscle HIF-1α Results in Altered Exercise Endurance
Open accessAbstract
The physiological flux of oxygen is extreme in exercising skeletal muscle. Hypoxia is thus a critical parameter in muscle function, influencing production of ATP, utilization of energy-producing substrates, and manufacture of exhaustion-inducing metabolites. Glycolysis is the central source of anaerobic energy in animals, and this metabolic pathway is regulated under low-oxygen conditions by the transcription factor hypoxia-inducible factor 1alpha (HIF-1alpha). To determine the role of HIF-1alpha in regulating skeletal muscle function, we tissue-specifically deleted the gene encoding the factor in skeletal muscle. Significant exercise-induced changes in expression of genes are decreased or absent in the skeletal-muscle HIF-1alpha knockout mice (HIF-1alpha KOs); changes in activities of glycolytic enzymes are seen as well. There is an increase in activity of rate-limiting enzymes of the mitochondria in the muscles of HIF-1alpha KOs, indicating that the citric acid cycle and increased fatty acid oxidation may be compensating for decreased flow through the glycolytic pathway. This is corroborated by a finding of no significant decreases in muscle ATP, but significantly decreased amounts of lactate in the serum of exercising HIF-1alpha KOs. This metabolic shift away from glycolysis and toward oxidation has the consequence of increasing exercise times in the HIF-1alpha KOs. However, repeated exercise trials give rise to extensive muscle damage in HIF-1alpha KOs, ultimately resulting in greatly reduced exercise times relative to wild-type animals. The muscle damage seen is similar to that detected in humans in diseases caused by deficiencies in skeletal muscle glycogenolysis and glycolysis. Thus, these results demonstrate an important role for the HIF-1 pathway in the metabolic control of muscle function.
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Low levels of HIF-1α in skeletal muscle resulted in a more altered phenotype in a mouse model, with an impaired exercise response.
“low levels of HIF-1α in skeletal muscle resulted in a more altered phenotype in a mouse model, with an impaired exercise response [77]”
From Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting (2023) · cites this paper as [77]
The Abstract reports that skeletal-muscle HIF-1α knockout mice developed muscle damage and greatly reduced exercise times after repeated trials, supporting an impaired exercise response in that setting. But the Results/Discussion (Figures 6 and 7; page unavailable) also report greater initial endurance in swimming and uphill running. The unqualified claim omits that exercise-dependent distinction. (LLM, conf=0.85)
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- Authors
- Mason, S. D., Howlett, R. A., Kim, M. J., Olfert, I. M., Hogan, M. C., McNulty, W., Hickey, R. P., Wagner, P. D., Kahn, C. R., Giordano, F. J., & Johnson, R. S.
- Affiliations
- University of California San Diego (US)
- Yale University (US)
- Harvard University (US)
- Corresponding author
- Johnson, Randall S
- Venue
- PLoS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2004-08-24
- Volume
- 2
- Issue
- 10
- Pages
- e288
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- PMC
- PMC514537
- OpenAlex
- W1975234288
- Cited by
- 210
- References
- 23
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 9 · 2023: 9 · 2022: 6 · 2021: 5 · 2020: 8 · 2019: 8 · 2018: 7 · 2017: 9 · 2016: 10 · 2015: 13 · 2014: 14 · 2013: 11 · 2012: 12
- FWCI
- 27.35
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Biology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Topics
- Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- HIF-1α, hypoxia-inducible factor, skeletal muscle, exercise endurance, glycolysis, mitochondrial metabolism, fatty acid oxidation, TCA cycle, muscle damage, lactate, exercise-induced gene expression
- MeSH terms
- Adenosine Triphosphate, Alleles, Animals, Hypoxia, Creatine Kinase, Crosses, Genetic, Physical Exertion, Gene Expression Regulation, Genotype, Glucose, Glycogen, Glycolysis, Hematocrit, Hemoglobins, Male, Mice, Inbred C57BL, Microscopy, Electron, Oxygen, Physical Conditioning, Animal, Promoter Regions, Genetic, Polymerase Chain Reaction, Gene Deletion, Mice, Knockout, Muscle, Skeletal, Lactic Acid, Reverse Transcriptase Polymerase Chain Reaction, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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