Baf60c drives glycolytic metabolism in the muscle and improves systemic glucose homeostasis through Deptor-mediated Akt activation
Open accessAbstract
A shift from oxidative to glycolytic metabolism has been associated with skeletal muscle insulin resistance in type 2 diabetes. However, whether this metabolic switch is deleterious or adaptive remains under debate, in part because of a limited understanding of the regulatory network that directs the metabolic and contractile specification of fast-twitch glycolytic muscle. Here we show that Baf60c (also called Smarcd3), a transcriptional cofactor enriched in fast-twitch muscle, promotes a switch from oxidative to glycolytic myofiber type through DEP domain-containing mTOR-interacting protein (Deptor)-mediated Akt activation. Muscle-specific transgenic expression of Baf60c activates a program of molecular, metabolic and contractile changes characteristic of glycolytic muscle. In addition, Baf60c is required for maintaining glycolytic capacity in adult skeletal muscle in vivo. Baf60c expression is significantly lower in skeletal muscle from obese mice compared to that from lean mice. Activation of the glycolytic muscle program by transgenic expression of Baf60c protects mice from diet-induced insulin resistance and glucose intolerance. Further mechanistic studies revealed that Deptor is induced by the Baf60c-Six4 transcriptional complex and mediates activation of Akt and glycolytic metabolism by Baf60c in a cell-autonomous manner. This work defines a fundamental mechanism underlying the specification of fast-twitch glycolytic muscle and illustrates that the oxidative-to-glycolytic metabolic shift in skeletal muscle is potentially adaptive and beneficial in the diabetic state.
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One SNP associated with k in moderate-to-severe COPD patients was located in the DEPTOR gene, which is associated with regulation of contractile properties of glycolytic muscles.
“Among them, one SNPs was located in the DEPTOR gene, of particular interest as it is associated with the regulation of the contractile properties of glycolytic muscles [151].”
From Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting (2023) · cites this paper as [151]
The paper reports that Deptor is enriched in glycolytic muscles and mediates BAF60c-driven AKT activation and glycolytic metabolism (Abstract; page unavailable). It attributes the observed contractile changes to BAF60c, but does not establish that Deptor itself regulates contractile properties. The COPD SNP finding is the citing authors’ own result, not a finding attributed to this source. (LLM, conf=0.84)
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References 38 · Cited by 146
Research works printed but not linked: 27
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- Authors
- Meng, Z.-X., Li, S., Wang, L., Ko, H. J., Lee, Y., Jung, D. Y., Okutsu, M., Yan, Z., Kim, J. K., & Lin, J. D.
- Affiliations
- University of Michigan (US)
- University of Massachusetts Chan Medical School (US)
- University of Virginia (US)
- Corresponding author
- Lin, Jiandie D
- ORCID
- Venue
- Nature Medicine
- Published
- 2013-04-07
- Volume
- 19
- Issue
- 5
- Pages
- 640-645
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC3650110
- OpenAlex
- W2001985793
- Cited by
- 146
- References
- 38
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 13 · 2023: 17 · 2022: 12 · 2021: 11 · 2020: 10 · 2019: 6 · 2018: 18 · 2017: 12 · 2016: 13 · 2015: 8 · 2014: 6 · 2013: 3
- FWCI
- 4.48
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Michigan
- National Institute of Diabetes and Digestive and Kidney Diseases (DK020572, U24DK093000, P60DK020572, R01DK080756, DK-077086, DK089503, R01DK095151, DK095151, R01DK077086, P30DK020572, P30DK089503)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR050429, AR 050429)
- Topics
- 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
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- Baf60c, SMARCD3, DEPTOR, Akt activation, glucose homeostasis, insulin resistance, type 2 diabetes, SIX4, mTOR signaling, high-fat diet, obesity
- MeSH terms
- Animals, Chromosomal Proteins, Non-Histone, Enzyme Activation, Glucose, Glycolysis, Homeostasis, Humans, Insulin Resistance, Mice, Transgenic, Muscle Proteins, Muscles, Physical Conditioning, Animal, Transcription Factors, Cluster Analysis, Muscle, Skeletal, Transgenes, Intracellular Signaling Peptides and Proteins, Proto-Oncogene Proteins c-akt, Mice, TOR Serine-Threonine Kinases
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