OBJECTIVE: Inactivity and inflammation are linked to obesity and insulin resistance. It was hypothesized that MyD88 (mediates inflammation) knockout from muscle (MusMyD88-/- ) would prevent, whereas miR146a-/- (MyD88 inhibitor) would exacerbate, inactivity-induced metabolic disturbances. METHODS: Cre-control, MusMyD88-/- , and miR146a-/- mice were given running wheels for 5 weeks to model an active phenotype. Afterward, half were placed into a small mouse cage (SMC) to restrict movement for 8 days. Body composition, muscle (3 H)2-deoxyglucose uptake, visceral fat histology, and tissue weight (hind limb muscles, visceral fat, and liver) were assessed. In skeletal muscle and visceral fat, RNA sequencing and mitochondrial function were performed on female MusMyD88-/- and Cre-control SMC mice. RESULTS: The SMC induced adiposity, hyperinsulinemia, and muscle insulin-stimulated glucose uptake, which was worsened in miR146a-/- mice. In females, MusMyD88-/- mice were protected. Female MusMyD88-/- mice during the SMC period (vs. Cre-control) exhibited higher Igf1 and decreased Ip6k3 and Trim63 muscle expression. Visceral fat transcript changes corresponded to improved lipid metabolism, decreased adipose expansion (Gulp1↑, Anxa2↓, Ehd1↓) and meta-inflammation (Hmox1↓), and increased beiging (Fgf10↑). Ralgapa2, negative regulator of GLUT4 translocation, and inflammation-related gene 993011J21Rik2 were decreased in both muscle and fat. CONCLUSIONS: Whole-body miR146a-/- exacerbated inactivity-induced fat gain and muscle insulin resistance, whereas MusMyD88-/- prevented insulin resistance in female mice.
OBJECTIVE: Inactivity and inflammation are linked to obesity and insulin resistance. It was hypothesized that MyD88 (mediates inflammation) knockout from muscle (MusMyD88-/- ) would prevent, whereas miR146a-/- (MyD88 inhibitor) would exacerbate, inactivity-induced metabolic disturbances. METHODS: Cre-control, MusMyD88-/- , and miR146a-/- mice were given running wheels for 5 weeks to model an active phenotype. Afterward, half were placed into a small mouse cage (SMC) to restrict movement for 8 days. Body composition, muscle (3 H)2-deoxyglucose uptake, visceral fat histology, and tissue weight (hind limb muscles, visceral fat, and liver) were assessed. In skeletal muscle and visceral fat, RNA sequencing and mitochondrial function were performed on female MusMyD88-/- and Cre-control SMC mice. RESULTS: The SMC induced adiposity, hyperinsulinemia, and muscle insulin-stimulated glucose uptake, which was worsened in miR146a-/- mice. In females, MusMyD88-/- mice were protected. Female MusMyD88-/- mice during the SMC period (vs. Cre-control) exhibited higher Igf1 and decreased Ip6k3 and Trim63 muscle expression. Visceral fat transcript changes corresponded to improved lipid metabolism, decreased adipose expansion (Gulp1↑, Anxa2↓, Ehd1↓) and meta-inflammation (Hmox1↓), and increased beiging (Fgf10↑). Ralgapa2, negative regulator of GLUT4 translocation, and inflammation-related gene 993011J21Rik2 were decreased in both muscle and fat. CONCLUSIONS: Whole-body miR146a-/- exacerbated inactivity-induced fat gain and muscle insulin resistance, whereas MusMyD88-/- prevented insulin resistance in female mice.
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