Effects of a high fat diet and Metformin on skeletal muscle membrane proteins and fiber size in young mice

Abstract

A prolonged high fat diet (HFD) is known to impair insulin signaling in skeletal muscle. Specifically, HFD reduces caveolin‐3, Akt activation, and GLUT‐4 translocation to the membrane. Type II diabetes results in the loss of sarcolemmal proteins of the dystrophin‐glycoprotein complex (DGC), particularly dystrophin and nNOS. However, the effect of HFD on DGC proteins is unknown. We hypothesized that HFD would cause translocation of DGC proteins away from the membrane. We further postulated that Metformin, an oral anti‐diabetic drug, would alleviate translocation of DGC proteins. To test our hypotheses, 8 week old C57Bl‐6 mice were fed a high fat diet for 14 weeks (n=8). After 9 weeks, mice were also given either PBS (n=4) or Metformin (n=4) for the remaining 5 weeks. Soleus muscle fiber cross sectional area (CSA) and DGC protein expression were quantified using immunohistochemistry assays. Surprisingly, we found a marked increase in fiber CSA that was normalized by Metformin. HFD resulted in a small decrease of dystrophin membrane expression with no change in nNOS, while the Metformin group expressed normal levels. These findings indicate that the DGC may undergo only minor functional changes in young mice fed a short term HFD, which are similar findings seen with muscle fiber hypertrophy. We postulate that intact DGC proteins may help preserve insulin signaling during short term HFD. Our future research will therefore focus on understanding how insulin signaling (e.g., IRS‐1, mTOR) might be preserved, and the point at which intact muscle insulin pathways in young mice become perturbed with prolonged HFD. This work was supported in part by ADA grant 1–10‐JF‐54 and AHA 12BGIA9050003 (to C.W).