제2형 당뇨병 마우스의 골격근 위축에 대한 C-peptide의 효과

Abstract

Type 2 diabetes mellitus is a chronic metabolic disease characterized by hyperglycemia caused by impaired insulin secretion and increased insulin resistance. Type 2 diabetes patients account for 90% of the total diabetic population. Muscle atrophy is one of the complications of Type 2 diabetes. Muscle atrophy occurs when protein degradation exceeds protein synthesis. In diabetic conditions, muscle loss can lead to a decline in physical function and a decrease in the quality of life. However, as of now, exercise therapy is the only known treatment for muscle atrophy. C-peptide is secreted in equimolar amounts with insulin from the pancreas when proinsulin is cleaved into insulin and C-peptide. C-peptide has been reported to have various biological functions, but its effects of on muscle tissue are unknown. Therefore, in this study, we investigated the effects of C-peptide on skeletal muscle atrophy in both normal mice (C57BL/6J) and type 2 diabetic mice (db/db). We treated normal mice and type 2 diabetic mice with low and high concentrations of C-peptide, and the untreated group was administered an equivalent amount of saline. As a result, there were no changes in the weight and the weight of organ tissues caused by C-peptide in all mice. Additionally, there were no significant differences in fasting blood glucose concentrations and serum C-peptide concentrations with vehicle and C-peptide treatment group. On the other hand, the grip strength was significantly improved in the mice treated with a high dose of C-peptide compared to the control group. Moreover, the tibialis anterior muscles were significantly increased by C-peptide injection in control mice. To elucidate the mechanisms supporting the observed improvements in muscle mass and function, a western blot experiment was conducted using the tibialis anterior muscle. The results of the experiment demonstrated that C-peptide increased the phosphorylation of Akt, which in turn blocked the nuclear translocation of Foxo, resulting in a significant reduction in the expression of major protein degradation markers such as MuRF1 and Atrogin-1. Additionally, phosphorylation of protein synthesis-related markers P70S6K and 4E-BP1 was significantly decreased in the db/db mice group, while C-peptide led to a marked elevation in the phosphorylation of P70S6K1 in both control and diabetic mice. In control mice, the phosphorylation of 4E-BP1 was significantly increased. In summary, while C-peptide did not show significant effects on muscle mass and function improvement, it inhibited muscle protein degradation in vivo and increased muscle protein synthesis in db/db mice. Moreover, C-peptide augmented muscle mass and function in normal conditions, inhibited protein degradation and increased protein synthesis. Furthermore, upon conducting transcriptome analysis, the common transcriptomic responses in both types of mice by C-peptide were found to be related to protein ubiquitination and inflammation-associated reactions. In conclusion, this study suggests that C-peptide may contribute to the improvement for muscle atrophy in type 2 diabetes and may help improve muscle mass and function in normal conditions.