MyD88 Signaling is Necessary for Physical Inactivity-Induced Skeletal Muscle Inflammation, Ceramide Biosynthesis and Insulin Resistance

Abstract

Physical inactivity leads to insulin resistance thereby increasing the risk of metabolic disorders (e.g. diabetes). Peripheral insulin resistance is frequently accompanied with impaired skeletal muscle insulin signaling. Evidence suggests that the myeloid differentiation primary response 88 (MyD88) pathway, and subsequent upregulation of skeletal muscle inflammation and ceramide biosynthesis may be a critical mediator of skeletal muscle insulin resistance with physical inactivity. This information will be important to decipher in the development of mechanism-based treatments to preserve muscle metabolic health in inactive adults. We hypothesize that activation of the MyD88 pathway is important in the production of skeletal muscle inflammation and ceramide biosynthesis and thus insulin resistance following a period of physical inactivity. PURPOSE: To determine if the MyD88 pathway is the cause of skeletal muscle inflammation, ceramide biosynthesis and insulin resistance with physical inactivity, we studied a mouse model with blocked MyD88 signaling that was subjected to physical inactivity (hindlimb unloading). METHODS: Groups of adult female wild type (WT) and MyD88 KO mice served as an ambulatory control or hindlimb unloaded (HU; tail suspension) for 14-days. At day 13, tail blood samples were collected after an overnight fast and after a glucose tolerance test (GTT). Following 14 days of HU, mice were fasted and culled for soleus muscle dissection for expression of key protein markers related to inflammation (NFκB signaling, IL6), ceramide biosynthesis signaling (SPT2) and insulin resistance (Akt signaling). RESULTS: 14-days of HU resulted in upregulation of skeletal muscle inflammation, ceramide biosynthesis signaling and insulin resistance (Akt signaling and GTT) in WT mice (P<0.05). However, MyD88 KO mice maintained insulin sensitivity following 14-days of HU. These data in MyD88 KO mice were also supported by levels of skeletal muscle inflammation and ceramide biosynthesis that were similar to MyD88 KO ambulatory control mice (P>0.05). CONCLUSION: These results support the hypothesis that the MyD88 pathway mediates skeletal muscle inflammation, ceramide biosynthesis and insulin resistance that is caused by short-term physical inactivity. Supported by the University of Utah’s Diabetes and Metabolism Center.