Adult skeletal muscle deletion of Mitofusin 1 and 2 impedes exercise performance and training capacity
Open accessAbstract
Endurance exercise has been shown to be a positive regulator of skeletal muscle metabolic function. Changes in mitochondrial dynamics (fusion and fission) have been shown to influence mitochondrial oxidative capacity. We therefore tested whether genetic disruption of mitofusins (Mfns) affected exercise performance in adult skeletal muscle. We generated adult-inducible skeletal muscle-specific Mfn1 (iMS-Mfn1KO), Mfn2 (iMS-Mfn2KO), and Mfn1/2 (iMS-MfnDKO) knockout mice. We assessed exercise capacity by performing a treadmill time to exhaustion stress test before deletion and up to 8 wk after deletion. Analysis of either the iMS-Mfn1KO or the iMS-Mfn2KO did not reveal an effect on exercise capacity. However, analysis of iMS-MfnDKO animals revealed a progressive reduction in exercise performance. We measured individual electron transport chain (ETC) complex activity and observed a reduction in ETC activity in both the subsarcolemmal and intermyofibrillar mitochondrial fractions specifically for NADH dehydrogenase (complex I) and cytochrome- c oxidase (complex IV), which was associated with a decrease in ETC subunit expression for these complexes. We also tested whether voluntary exercise training would prevent the decrease in exercise capacity observed in iMS-MfnDKO animals ( n = 10/group). However, after 8 wk of training we did not observe any improvement in exercise capacity or ETC subunit parameters in iMS-MfnDKO animals. These data suggest that the decrease in exercise capacity observed in the iMS-MfnDKO animals is in part the result of impaired ETC subunit expression and ETC complex activity. Taken together, these results provide strong evidence that mitochondrial fusion in adult skeletal muscle is important for exercise performance. NEW & NOTEWORTHY This study is the first to utilize an adult-inducible skeletal muscle-specific knockout model for Mitofusin (Mfn)1 and Mfn2 to assess exercise capacity. Our findings reveal a progressive decrease in exercise performance with Mfn1 and Mfn2 deletion. The decrease in exercise capacity was accompanied by impaired oxidative phosphorylation specifically for complex I and complex IV. Furthermore, voluntary exercise training was unable to rescue the impairment, suggesting that normal fusion is essential for exercise-induced mitochondrial adaptations.
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Mitochondrial fusion proteins are essential for the maintenance of mitochondrial and skeletal muscle health.
“Taken altogether, the available literature clearly indicates that mitochondrial fusion proteins are essential for the maintenance of mitochondrial and skeletal muscle health.”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [35]
Deletion of both Mfn1 and Mfn2 in adult skeletal muscle results in a major decrease in exercise performance in mice.
“Deletion of both Mfn1 and Mfn2 in adult skeletal muscle resulted in a major decrease in exercise performance, indicating that mitochondrial fusion is essential to muscle performance in mice [35].”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [35]
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- Authors
- Bell, M. B., Bush, Z., McGinnis, G. R., & Rowe, G. C.
- Affiliations
- University of Alabama at Birmingham (US)
- Corresponding author
- Rowe, Glenn C.
- Venue
- Journal of Applied Physiology
- Publisher
- American Physiological Society
- Published
- 2019-02-01
- Volume
- 126
- Issue
- 2
- Pages
- 341-353
- ISSN
- 0161-7567 (ISSN-L)
- 8750-7587
- 1522-1601
- PMC
- PMC6397407
- OpenAlex
- W2893688568
- Cited by
- 62
- References
- 64
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 5 · 2023: 13 · 2022: 12 · 2021: 10 · 2020: 5 · 2019: 1
- FWCI
- 1.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Applied Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (AR062128)
- HHS | NIH | National Institute of Child Health and Human Development (NICHD) (HD071866)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- mitofusin 1, mitofusin 2, mitochondrial fusion, skeletal muscle, exercise capacity, endurance exercise, electron transport chain, complex I, cytochrome c oxidase, oxidative phosphorylation, mitochondrial dynamics, mitochondrial biogenesis
- MeSH terms
- Gait Analysis, Age Factors, Animals, Electron Transport Complex IV, Female, Genotype, Mice, Inbred C57BL, Mitochondria, Muscle, Muscle Contraction, NADH Dehydrogenase, Oxidative Phosphorylation, Phenotype, Physical Conditioning, Animal, Exercise Tolerance, Mice, Knockout, Muscle, Skeletal, GTP Phosphohydrolases
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