Intramyocellular ceramides and skeletal muscle mitochondrial respiration are partially regulated by Toll-like receptor 4 during hindlimb unloading
Open accessAbstract
Physical inactivity and disuse result in skeletal muscle metabolic disruption, including insulin resistance and mitochondrial dysfunction. The role of the Toll-like receptor 4 (TLR4) signaling pathway in contributing to metabolic decline with muscle disuse is unknown. Therefore, our goal was to determine whether TLR4 is an underlying mechanism of insulin resistance, mitochondrial dysfunction, and skeletal muscle ceramide accumulation following muscle disuse in mice. To address this hypothesis, we subjected ( n = 6–8/group) male WT and TLR4−/−mice to 2 wk of hindlimb unloading (HU), while a second group of mice served as ambulatory wild-type controls (WT CON, TLR4−/−CON). Mice were assessed for insulin resistance [homeostatic model assessment-insulin resistance (HOMA-IR), glucose tolerance], and hindlimb muscles (soleus and gastrocnemius) were used to assess muscle sphingolipid abundance, mitochondrial respiration [respiratory control ratio (RCR)], and NF-κB signaling. The primary finding was that HU resulted in insulin resistance, increased total ceramides, specifically Cer18:0 and Cer20:0, and decreased skeletal muscle mitochondrial respiration. Importantly, TLR4−/−HU mice were protected from insulin resistance and altered NF-κB signaling and were partly resistant to muscle atrophy, ceramide accumulation, and decreased RCR. Skeletal muscle ceramides and RCR were correlated with insulin resistance. We conclude that TLR4 is an upstream regulator of insulin sensitivity, while partly upregulating muscle ceramides and worsening mitochondrial respiration during 2 wk of HU.
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Signalling initiated by TLR-4 and TNF-α receptor results in activation of the NFkB pathway, which has been linked to reduced mitochondrial respiration and suppressed activation of transcriptional regulators that promote mitochondrial biogenesis and the shift towards a muscle oxidative phenotype.
“In support of this latter idea, signalling initiated by toll-like receptor-4 (TLR-4) and the tumor necrosis factor-α (TNF-α) receptor results in activation of the NFkB pathway, which has been linked to reduced mitochondrial respiration and suppressed activation of transcriptional regulators that promote mitochondrial biogenesis and the shift towards a muscle oxidative phenotype [23, 24].”
From Proinflammatory NFkB signalling promotes mitochondrial dysfunction in skeletal muscle in response to cellular fuel overloading (2019) · cites this paper as [23]
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Targeting Intramyocellular Lipids to Improve Aging Muscle Function
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- Authors
- Kwon, O. S., Nelson, D. S., Barrows, K. M., O'Connell, R. M., & Drummond, M. J.
- Affiliations
- George E. Wahlen Department of VA Medical Center (US)
- University of Utah (US)
- Department of Pathology, University of Utah, Salt Lake City, Utah; and
- Corresponding author
- Drummond, Micah J.
- Venue
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
- Publisher
- American Physiological Society
- Published
- 2016-11-01
- Volume
- 311
- Issue
- 5
- Pages
- R879-R887
- ISSN
- 0363-6119 (ISSN-L)
- 1522-1490
- PMC
- PMC5130578
- OpenAlex
- W2510273707
- Cited by
- 24
- References
- 50
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 5 · 2019: 4 · 2018: 2 · 2017: 4 · 2016: 1
- FWCI
- 1.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute on Aging (U.S. National Institute on Aging)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- TLR4, hindlimb unloading, muscle disuse, insulin resistance, sphingolipids, NF-κB signaling, muscle atrophy, respiratory control ratio, soleus muscle, gastrocnemius, TLR4 knockout mice
- MeSH terms
- Animals, Ceramides, Male, Mice, Inbred C57BL, Mitochondria, Muscle, Muscular Atrophy, Oxygen, Mice, Knockout, Muscle, Skeletal, Cell Respiration, Hindlimb Suspension, Toll-Like Receptor 4, Mice
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