Remodeling of skeletal muscle mitochondrial proteome with high-fat diet involves greater changes to β-oxidation than electron transfer proteins in mice
Open accessAbstract
Excess fat intake can increase lipid oxidation and expression of mitochondrial proteins, indicating remodeling of the mitochondrial proteome. Yet intermediates of lipid oxidation also accumulate, indicating a relative insufficiency to completely oxidize lipids. We investigated remodeling of the mitochondrial proteome to determine mechanisms of changes in lipid oxidation following high-fat feeding. C57BL/6J mice consumed a high-fat diet (HFD, 60% fat from lard) or a low-fat diet (LFD, 10% fat) for 12 wk. Mice were fasted for 4 h and then anesthetized by pentobarbital sodium overdose for tissue collection. A mitochondrial-enriched fraction was prepared from gastrocnemius muscles and underwent proteomic analysis by high-resolution mass spectrometry. Mitochondrial respiratory efficiency was measured as the ratio of ATP production to O 2 consumption. Intramuscular acylcarnitines were measured by liquid chromatography-mass spectrometry. A total of 658 mitochondrial proteins were identified: 40 had higher abundance and 14 had lower abundance in mice consuming the HFD than in mice consuming the LFD. Individual proteins that changed with the HFD were primarily related to β-oxidation; there were fewer changes to the electron transfer system. Gene set enrichment analysis indicated that the HFD increased pathways of lipid metabolism and β-oxidation. Intramuscular concentrations of select acylcarnitines (C18:0) were greater in the HFD mice and reflected dietary lipid composition. Mitochondrial respiratory ATP production-to-O 2 consumption ratio for lipids was not different between LFD and HFD mice. After the 60% fat diet, remodeling of the mitochondrial proteome revealed upregulation of proteins regulating lipid oxidation that was not evident for all mitochondrial pathways. The accumulation of lipid metabolites with obesity may occur without intrinsic dysfunction to mitochondrial lipid oxidation.
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Muscle β-oxidation increases in response to a high-fat diet, but excessive lipid content or duration can exceed this capacity, leading to ectopic lipid accumulation and impaired lipid metabolism.
“muscle β-oxidation increases in response to a high-fat diet (HFD) [83–86], although excessive lipid content or duration of such diets can exceed this capacity, leading to ectopic lipid accumulation and impaired lipid metabolism [87–91].”
From Targeting Intramyocellular Lipids to Improve Aging Muscle Function (2025) · cites this paper as [83]
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- Authors
- Dasari, S., Newsom, S. A., Ehrlicher, S. E., Stierwalt, H. D., & Robinson, M. M.
- Affiliations
- Mayo Clinic (US)
- Oregon State University (US)
- Corresponding author
- Robinson, Matthew M.
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2018-10-01
- Volume
- 315
- Issue
- 4
- Pages
- E425-E434
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- PMC
- PMC6230708
- OpenAlex
- W2807147346
- Cited by
- 21
- References
- 44
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 6 · 2020: 2 · 2019: 3 · 2018: 1
- FWCI
- 1.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK103829)
- HHS | NIH | National Center for Advancing Translational Sciences (NCATS) (KL2TR002370)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Keywords
- high-fat diet, skeletal muscle, lipid oxidation, fatty acid beta-oxidation, electron transfer proteins, acylcarnitines, gastrocnemius, obesity, lipid metabolism, dietary fat composition
- MeSH terms
- Adenosine Triphosphate, Animals, Carnitine, Chromatography, Liquid, Electron Transport, Insulin Resistance, Male, Mice, Inbred C57BL, Mitochondria, Muscle, Oxidation-Reduction, Oxygen Consumption, Protein Processing, Post-Translational, Mass Spectrometry, Muscle, Skeletal, Diet, Fat-Restricted, Cell Respiration, Proteome, Mitochondrial Proteins, Proteomics, Electron-Transferring Flavoproteins, Lipid Metabolism, Mice, Tandem Mass Spectrometry, Diet, High-Fat
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