title: Intramyocellular ceramides and skeletal muscle mitochondrial respiration are partially regulated by Toll-like receptor 4 during hindlimb unloading.
abstract: 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.
authors: Geriatric Research, Education, and Clinical Center, George E. Whalen Veterans Affairs Medical Center, Salt Lake City, Utah.
authors: Oh Sung
authors: OS
authors: Kwon
authors: Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah.
authors: Daniel S
authors: DS
authors: Nelson
authors: Department of Physical Therapy, University of Utah, Salt Lake City, Utah.
authors: Katherine M
authors: KM
authors: Barrows
authors: Department of Pathology, University of Utah, Salt Lake City, Utah; and.
authors: Ryan M
authors: RM
authors: O'Connell
authors: Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah; micah.drummond@hsc.utah.edu.|Department of Physical Therapy, University of Utah, Salt Lake City, Utah.|Department of Pathology, University of Utah, Salt Lake City, Utah; and.|Division of Diabetes, Metabolism and Endocrinology, University of Utah, Salt Lake City, Utah.
authors: Micah J
authors: MJ
authors: Drummond
mesh_terms: D000818:Animals; D019069:Cell Respiration; D002518:Ceramides / Q000378:metabolism*; D019417:Hindlimb Suspension / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology*; D009133:Muscular Atrophy / Q000473:pathology / Q000503:physiopathology*; D010100:Oxygen / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D002518:Ceramides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D010100:Oxygen
keywords: inflammation; insulin resistance; lipids; physical inactivity; sphingolipids