Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism
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Significance: Many theories regarding the causes of insulin resistance in skeletal muscle center on the ability of muscle to oxidize fat, with evidence supporting either decreased or increased fatty acid oxidation (FAO) as causal to insulin resistance. Inhibition of fatty acid transport into mitochondria specifically in mouse muscle results in a rather remarkable phenotype. Despite an accumulation of lipids in muscle, insulin sensitivity is maintained. The muscle responds to decreased FAO by adapting muscle metabolism to use other fuel sources, and by an increased reliance upon peroxisomal fat oxidation. There is also an increase in mitochondrial biogenesis. At the whole-body level, the mice seem to enter an energy conservation mode with reduced activity, energy expenditure, and resistance to diet-induced obesity.
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In carnitine palmitoyltransferase 1B knockout mice, intramyocellular lipid accumulation may not directly induce insulin resistance, but the animals exhibited muscle injury, disrupted metabolism and functional impairment that were partially ameliorated by a low-fat diet.
“A set of interesting experiments in transgenic mice (carnitine palmitoyltransferase 1B knockout) have suggested that IMCL accumulation may not directly induce insulin-resistance, but even these animals’ exhibited markers of muscle injury, disrupted metabolism and functional impairment, which were partially ameliorated by a low-fat diet [67–69].”
From Targeting Intramyocellular Lipids to Improve Aging Muscle Function (2025) · cites this paper as [69]
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“Multiple studies have documented that defects in peroxisome biogenesis [57–59] or mitochondrial function [60,61] coincide with an increase in the volume of the other subcellular compartment (for details, see Sections 4.”
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Self-citationTargeting Intramyocellular Lipids to Improve Aging Muscle Function
Russ, D. W., Manickam, R., & Tipparaju, S. M. (2025) · Lipids in Health and Disease · doi:10.1186/s12944-025-02622-6 · Cited by 15 · see citing works
- Authors
- Wicks, S. E., Vandanmagsar, B., Haynie, K. R., Fuller, S. E., Warfel, J. D., Stephens, J. M., Wang, M., Han, X., Zhang, J., Noland, R. C., & Mynatt, R. L.
- Affiliations
- Pennington Biomedical Research Center (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-06-08
- Volume
- 112
- Issue
- 25
- Pages
- E3300-9
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4485116
- OpenAlex
- W1601325022
- Cited by
- 131
- References
- 49
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 14 · 2023: 6 · 2022: 9 · 2021: 17 · 2020: 14 · 2019: 24 · 2018: 6 · 2017: 10 · 2016: 9
- FWCI
- 6.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Civil War Book Review (submittedVersion)
- Funders
- American Diabetes Association (1-10-BS-129)
- HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (R01DK089641, R01DK103860, P30-DK072476)
- HHS | NIH | National Institute of General Medical Sciences (P20-GM103528)
- HHS | NIH | National Center for Complementary and Alternative Medicine (T32 AT004094)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- mitochondrial fatty acid oxidation, carnitine palmitoyltransferase 1, skeletal muscle metabolism, intramyocellular lipid, insulin resistance, lipotoxicity, mitochondrial biogenesis, amino acid catabolism, AMPK, PGC-1α, free fatty acids, diacylglycerol, ceramide, obesity resistance
- MeSH terms
- Adaptation, Physiological, Animals, Carnitine O-Palmitoyltransferase, Fatty Acids, Nonesterified, Mitochondria, Muscle, Oxidation-Reduction, Mice, Knockout, Muscle, Skeletal, Mice
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