Abstract
The repair capacity of progenitor skeletal muscle satellite cells (SC) in Type 1 diabetes mellitus (T1DM) is decreased. This is associated with the loss of skeletal muscle function. In T1DM, the deficiency of C-peptide along with insulin is associated with an impairment of skeletal muscle functions such as growth, and repair, and is thought to be an important contributor to increased morbidity and mortality. Recently, cholesterol-lowering drugs (statins) have also been reported to increase the risk of skeletal muscle dysfunction. We hypothesised that C-peptide activates key signaling pathways in myoblasts, thus promoting cell survival and protecting against simvastatin-induced myotoxicity. This was tested by investigating the effects of C-peptide on the L6 rat myoblast cell line under serum-starved conditions. Results: C-peptide at concentrations as low as 0.03 nM exerted stimulatory effects on intracellular signaling pathways—MAP kinase (ERK1/2) and Akt. When apoptosis was induced by simvastatin, 3 nM C-peptide potently suppressed the apoptotic effect through a pertussis toxin-sensitive pathway. Simvastatin strongly impaired Akt signaling and stimulated the reactive oxygen species (ROS) production; suggesting that Akt signaling and oxidative stress are important factors in statin-induced apoptosis in L6 myoblasts. The findings indicate that C-peptide exerts an important protective effect against death signaling in myoblasts. Therefore, in T1DM, the deficiency of C-peptide may contribute to myopathy by rendering myoblast-like progenitor cells (involved in muscle regeneration) more susceptible to the toxic effects of insults such as simvastatin.
Highlights
In Type 1 diabetes mellitus (T1DM), impaired skeletal muscle health is observed and is termed diabetic myopathy (DMy) [1]
The present results show that C-peptide does suppress the inhibitory effect of simvastatin on Akt phosphorylation, and this protective effect on Akt stimulation persisted even in incubations with simvastatin and C-peptide lasting as long as 72 h
In view of the important functional effects of C-peptide on myoblasts reported in this study, it seems feasible that C-peptide might protect against the development of myopathy arising from damaging effects on myoblast-like satellite cells in T1DM patients who receive long-term treatment with statins
Summary
In Type 1 diabetes mellitus (T1DM), impaired skeletal muscle health is observed and is termed diabetic myopathy (DMy) [1]. This complication of T1DM is poorly studied but is associated with the progression of other diabetic complications and directly influences the development of co-morbidity, possibly due to the fact that skeletal muscle functions are the largest site for glucose uptake [2]. Changes to skeletal muscle health may have an impact on whole-body glucose homeostasis [1]. In uncontrolled T1DM, complete insulin deficiency contributes to rapid muscle protein loss [3] due to an imbalance between synthesis and breakdown where protein catabolism exceeds any increase in protein synthesis resulting from the release of amino acids from the degraded protein [4]. High glucose exerts a detrimental effect on mature skeletal muscle, and on satellite cell and myoblast proliferation and differentiation (reviewed in [1])
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