Insulin Resistance, Skeletal Muscle Extracellular Matrix Remodeling, And The Effect Of Exercise

Abstract

Extracellular matrix (ECM) remodeling in skeletal muscle is a potential mechanism linking obesity with metabolic dysfunction. It is also a constructive feature of skeletal muscle adaptation to exercise training. PURPOSE: To test the hypothesis that skeletal muscle ECM remodeling associated with insulin resistance can be minimized by exercise training. METHODS: Six-week-old male C57/BL6J mice (n=48) were divided into two groups, high-fat (60% calories from fat) diet (HF, n=36) and normal chow-fed control (C, n=12) group. After 12 weeks of feeding, HF mice developed insulin resistance, as confirmed by insulin and glucose tolerance tests (ITT and GTT). HF mice were then randomly assigned to three groups: high-fat diet only group (HFS, n=12), high-fat diet + aerobic exercise group (HF+AE, n=12), high-fat diet + resistance training group (HF+RT, n=12). The HF+AE and HF+RT groups were subject to aerobic (treadmill running) and resistive (vertical ladder climbing) training, for 12 weeks. After training, gastrocnemius muscle was harvested and analyzed for ECM factors using immunohistochemistry, ECM PCR array, and western blotting. ANOVA was performed to test the significance of group differences at p<0.05. RESULTS: High-fat feeding induced higher deposition of collagens (COLI, III and IV) in the skeletal muscle of HFS group, and increased gene and protein expression of MMP3, CDH1, ITGAL and SELL and decreased the expression of TIMP3 in HFS group, as compared to group C. These changes were minimized even reversed by either aerobic or resistance exercise training (mRNA fold change relative to C in HF+AE and HF+RT vs. HFS: MMP3, 1.1 and 1.6 vs. 2.6; CDH1, 1.7 and 1.1 vs. 2.0; ITGAL, 1.9 and -1.0 vs. 2.0; SELL, 1.4 and 1.0 vs. 2.1; TIMP3, 1.2 and -1.0 vs. -1.2; p<0.05). These effects were accompanied by a significant improvement in insulin sensitivity (GTT AUC glucose in mmol/l x 120 min: C, 27.2±3.0; HFS, 39.7 ± 7.0; HF+AE, 32.4± 7.5; HF+RT, 30.3± 6.1; p<0.05). CONCLUSION: Both aerobic and resistive exercise training can minimize changes in skeletal muscle ECM associated with insulin resistance. Skeletal muscle ECM remodeling may play a significant role in mediating the metabolic benefits of exercise training. This study was supported by National Nature Science Foundation of China (31470060).