title: MyD88 regulates physical inactivity-induced skeletal muscle inflammation, ceramide biosynthesis signaling, and glucose intolerance.
abstract: Physical inactivity in older adults is a risk factor for developing glucose intolerance and impaired skeletal muscle function. Elevated inflammation and ceramide biosynthesis have been implicated in metabolic disruption and are linked to Toll-like receptor (TLR)/myeloid differentiation primary response 88 (MyD88) signaling. We hypothesize that a physical inactivity stimulus, capable of inducing glucose intolerance, would increase skeletal muscle inflammation and ceramide biosynthesis signaling and that this response would be regulated by the TLR/MyD88 pathway. Therefore, we subjected wild-type (WT) and MyD88(-/-) mice to hindlimb unloading (HU) for 14 days or an ambulatory control period. We observed impaired glucose uptake, muscle insulin signaling (p-Akt), and increased markers of NF-κB signaling (p-IκBα), inflammation (p-JNK, IL-6), TLR4, and the rate-limiting enzyme of ceramide biosynthesis, SPT2, with HU WT (P < 0.05), but not in HU MyD88(-/-) mice. Concurrently, we found that 5 days of bed rest in older adults resulted in whole body glucose dysregulation, impaired skeletal muscle insulin signaling, and upregulation of muscle IL-6 and SPT2 (P < 0.05). Post-bed rest TLR4 abundance was tightly correlated with impaired postprandial insulin and glucose levels. In conclusion, MyD88 signaling is necessary for the increased inflammation, ceramide biosynthesis signaling, and compromised metabolic function that accompanies physical inactivity.
authors.affiliation: Departments of Physical Therapy.
authors.forename: Oh Sung
authors.initials: OS
authors.lastname: Kwon
authors.affiliation: Divisions of Nutrition and.
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Tanner
authors.affiliation: Departments of Physical Therapy.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Barrows
authors.affiliation: Pathology and.
authors.forename: Marah
authors.initials: M
authors.lastname: Runtsch
authors.affiliation: Exercise and Sport Science and Divisions of Nutrition and Diabetes, Metabolism and Endocrinology, University of Utah, Salt Lake City, Utah; and.
authors.forename: J David
authors.initials: JD
authors.lastname: Symons
authors.affiliation: Divisions of Nutrition and.
authors.forename: Thunder
authors.initials: T
authors.lastname: Jalili
authors.affiliation: Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Bikman
authors.affiliation: Diabetes, Metabolism and Endocrinology, University of Utah, Salt Lake City, Utah; and.
authors.forename: Donald A
authors.initials: DA
authors.lastname: McClain
authors.affiliation: Pathology and.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: O'Connell
authors.affiliation: Departments of Physical Therapy, Divisions of Nutrition and Diabetes, Metabolism and Endocrinology, University of Utah, Salt Lake City, Utah; and micah.drummond@hsc.utah.edu.
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Drummond
mesh_terms: D000368:Aged; D000818:Animals; D001510:Bed Rest / Q000009:adverse effects; D002518:Ceramides / Q000096:biosynthesis*; D005260:Female; D018149:Glucose Intolerance / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009043:Motor Activity / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000502:physiology*; D009220:Myositis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012146:Rest / Q000502:physiology
chemical_list: D002518:Ceramides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88
keywords: TLR4; bed rest; insulin resistance; metabolic disruption