Protein Degradative Processes Associated with Anabolic Dysregulation in Diabetic Skeletal Muscle

Skeletal muscle of obese Zucker rats function at higher rates of anabolism when compared to lean littermates, and are resistant to the anabolic effect of exercise. We recently determined that DEP domain containing mammalian target of rapamycin (mTOR)-interacting protein (DEPTOR), a potent negative binding partner of mTOR, is reduced in skeletal muscle of diabetic rats, suggesting that regulation of this protein may participate in the altered protein metabolism. The purpose of this investigation was to assess key regulators of DEPTOR expression, RING-box protein 1 (Rbx1) and beta-transducin repeat-containing protein (?-TrCP), in gastrocnemius muscle of rats with or without type 2 diabetes, with or without in vivo resistance exercise. We hypothesized that the reduced expression of DEPTOR would be accompanied by altered expression of Rbx1 and/or ?-TrCP. Tissues from thirty male Zucker rats (16 lean [L], 14 obese [F]) collected from previous studies were used for this investigation. Rats were subsequently assigned to sedentary ([S]; 8 LS, 6 FS) or resistance exercise ([E]; 8 LE, 8 FE) groups. Exercised rats participated in four progressive bouts, with increasing repetitions and loads, over 8 days.

Results indicate that DEPTOR mRNA levels were consistent with previously reported protein levels, with reduced content in LE compared to LS (p<0.05) and obese groups (FS and FE) not different than LE (p>0.05). ?-TrCP protein levels were not affected by exercise, but were higher (39%) in obese compared to lean animals; whereas, ?-TrCP mRNA content was 113% greater in FE compared to FS (p<0.05). There was a main effect of resistance exercise on Rbx1 protein content, where exercised animals had 30% lower levels of protein than sedentary animals. Further analysis revealed that Rbx1 protein content was suppressed by exercise in lean animals only (49% lower). A main effect of exercise was also observed for Rbx1 mRNA, where exercised animals displayed 47% higher levels than sedentary animals (p<0.05).

In conclusion, we speculate that the heightened anabolic function in obese animals may be partly due to increased protein levels of ?-TrCP, which may lead to suppressed DEPTOR levels and unrestricted mTOR activity. Additionally, the ?-TrCP /DEPTOR interaction may be a key culprit for the reported resistance to anabolic stimuli in diabetic skeletal muscle.