Diabetes and High-Fat Diet Induce Different Pathologies in Mouse Skeletal Muscle Extracellular Matrix

Abstract

Whether obesity and diabetes (DM) similarly affect composition and function of skeletal muscle extracellular matrix (ECM) has not been resolved. This study examines the effects of long term high fat diet (HFD) and DM on rodent skeletal muscle ECM were addressed. Five week old C57BL/6 male mice were randomly allocated to standard chow (control; n=26) or HFD (45% kcal fat; n=25). After 15 weeks chow and HFD mice were rendered diabetic (by low dose STZ, 65mg/kgx3d, I.P.) (DM, n=14; HFD+DM, n=14); nondiabetic mice acted as controls. Mice were euthanased after 30 weeks and plasma and quadriceps muscle were collected for analysis. Body weight and plasma insulin expectedly decreased with DM induction and increased with HFD (all p<0.05). High glucose occurred only in DM mice (∼14 mM; p<0.05), whereas only HFD increased muscle triglyceride (p<0.05). Both conditions induced a decrease in quadriceps weight and in grip strength performance (p<0.05). Quadriceps of DM mice showed increased CTGF/CCN2 (1.5-fold; p<0.05), TIMP-1 (2-fold; p<0.05), collagen-I (3-fold; p<0.05), -IV (2-fold; p<0.05), and -VI (2-fold; p<0.05) protein. In contrast, HFD induced a downregulation of CTGF/CCN2 (0.6-fold; p<0.05), MMP-1 (0.6-fold; p<0.05), and TIMP-2 (0.4-fold; p<0.05). In DM mice quadriceps centralized nuclei (p<0.05) and caspase 3 (protein; 1.5-fold; p<0.05) were increased, whereas caspase 3 was decreased in HFD (0.5-fold; p<0.05). Moreover, HFD induced a downregulation of ubiquitin ligase atrogin-1 protein (0.5-fold; p<0.05) and mRNA levels of serine/threonine kinase p70S6k (0.75-fold; p<0.05). Notably, no greater dysregulation of the muscle changes observed with DM alone or with HFD alone, was seen in HFD+DM mice. These data suggest that DM and HFD differentially affect skeletal muscle ECM: DM promotes a pro-fibrotic profile with signs of muscle damage, and HFD impairs regulatory protein turnover pathways, each inducing muscle dysfunction. Disclosure S.F. Martinez-Huenchullan: None. L.A. Ban: None. A. Tao: None. S.S. Sutanto: None. C. Tam: None. S. McLennan: None. S.M. Twigg: Advisory Panel; Self; Abbott. Consultant; Self; Abbott. Advisory Panel; Self; Novo Nordisk Inc., Sanofi-Aventis, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. Speaker's Bureau; Self; AstraZeneca, Merck Sharp & Dohme Corp.. Other Relationship; Self; Abbott.