Obesity impairs muscle function and skeletal muscle extracellular matrix

Skeletal muscle extracellular matrix (ECM) remodeling has been proposed as another feature of the pathogenic milieu associated with obesity and metabolic dysfunction. Whether muscle ECM is associated with impaired physical function in obese conditions is unknown. We developed a preclinical model to assess for muscle function-structure presence and relationships. C57BL/6 mice were fed high-fat diet (HFD) or regular chow for 5, 10 and 25 weeks. Non-invasive physiological tests (hang wire, hang mesh and grip strength) to assess neuromuscular function and motor coordination were performed. To account for the effects of body weight, hang wire and hang mesh test results were multiplied by weight. Genes related to ECM structure [collagens (COL)1, COL3, COL6A2, secreted protein and rich in cysteine (SPARC)], growth factors [transforming growth factor (TGF)B1, TGFB2, connective tissue growth factor (CTGF), vascular endothelial growth factor (VEGF), and muscle function [dystrophin (DMD (Dp147), calpain 3 (CPN3), β-dystroglycan (DAG1)] were measured in gastrocnemius muscle using real-time PCR. Two-way analysis of variance was performed to examine changes in physical function and gene expression with group and time effects. Compared with chow, HFD mice had impaired muscle strength and lower COL1, COL3, COL6, VEGF and CPN3 gene expression (all P<0.05). At 5 weeks, greater muscle COL3 (r2=0.48, P=0.02) and COL6 gene expression (r2=0.41, P=0.03) were each associated with physical impairment (hang wire) in high-fat fed animals; these associations were not seen at the later time points of 10 or 25 weeks. In conclusion, muscle function and motor co-ordination tests revealed that high-fat fed mice had impaired performance, which after only 5 weeks was associated with greater muscle ECM accumulation in large muscle. Our findings contribute to the growing body of evidence underlining the significance of skeletal muscle ECM in metabolic and whole-body dysfunction.