Abstract
Skeletal muscle extracellular matrix (ECM) remodelling has been proposed as a 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. C57BL/6 mice were fed a high-fat diet (HFD) or chow for 5, 10 and 25 weeks. Non-invasive physiological tests (hang wire, hang mesh and grip strength) to assess neuromuscular function and motor co-ordination were performed. Genes related to ECM structure (COL1, COL3, COL6A2, SPARC), growth factors (TGFB1, TGFB2, CTGF, VEGF) and muscle function (DMD (Dp147), CPN3, DAG1) were measured in gastrocnemius muscle using real-time PCR and COL1, 3 and 6 protein were measured by western immunoblot. Compared with chow, HFD mice had two to six-fold lower muscle strength (hang wire test; raw data and multiplied by body weight) at all time-points (P<0.001) and two-fold lower hang mesh and grip strength at 10 weeks (P<0.05). At 5 weeks, COL1, COL3 and COL6 gene expression, but not protein levels were three to eight-fold lower in HFD compared with chow. In the HFD group at 5 weeks, greater COL3 and 6 gene expression were associated with poorer hang wire performance. For the first time, our results demonstrate links between muscle ECM structure and physical function in obesity.
Highlights
Skeletal muscle comprises 40–50% of body weight and is essential for body movement, physical function and insulin-stimulated glucose uptake, all of which are impaired in obesity
This study examined potential links between muscle extracellular matrix (ECM) gene expression and impaired physical function in obese mice
We found that mice fed high-fat diet (HFD) for 5, 10 and 25 weeks had impaired anaerobic endurance and co-ordination as measured by hang wire test
Summary
Skeletal muscle comprises 40–50% of body weight and is essential for body movement, physical function and insulin-stimulated glucose uptake, all of which are impaired in obesity. A recently published overfeeding study found dramatic upregulation of mRNA levels in ECM genes (collagens I, III, IV, V and VI and SPARC) in muscle from lean males after moderate weight gain.. A recently published overfeeding study found dramatic upregulation of mRNA levels in ECM genes (collagens I, III, IV, V and VI and SPARC) in muscle from lean males after moderate weight gain.2 This body of evidence suggests a new role for skeletal muscle ECM remodelling in the pathophysiology of obesity and insulin resistance. Given the emerging role of muscle ECM remodelling in obesity and insulin resistance, and known structure–function relationships in muscular dystrophies, we investigated whether muscle ECM gene expression was associated with tests of anaerobic endurance and co-ordination in obese mice Mutations in genes encoding several dystrophin components result in disruption of this complex leading to muscular dystrophy. Given the emerging role of muscle ECM remodelling in obesity and insulin resistance, and known structure–function relationships in muscular dystrophies, we investigated whether muscle ECM gene expression was associated with tests of anaerobic endurance and co-ordination in obese mice
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