TISSUE INJURY AND REPAIR

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Introduction and Aims:In our previous studies we found that exercise partially prevents chronic kidney disease (CKD)-induced muscle atrophy.Effective therapeutic strategies to treat Chronic Kidney Disease (CKD)-induced muscle atrophy are urgently needed.Low frequency electrical stimulation (LFES) induces muscle contraction which mimics acupuncture and exercise, and may be effective in preventing muscle atrophy.Methods: CKD was induced in 20-25g mice by 5/6th nephrectomy.CKD and control mice were treated with LFES for 15 days.Results: LFES prevented soleus and EDL muscle weight loss in CKD mice ( p<0.05, LFES/CKD vs. CKD) as well as loss of hind-limb muscle grip.LFES countered the CKD-induced decline in the IGF-1 signaling pathway, leading to increased protein synthesis, decreased protein degradation and increased myogenesis markers.There is an acute (immediate) response phase during which inflammation cytokines (IFN and IL-6) increased.M1 macrophage markers ( pro-inflammation: IL-1β) were also increased acutely, but M2 markers (anti-inflammation: arg-1, IL-10 and IL-4) were increased 2-days after initiation of LFES.In addition, microRNA-1 and -206 were decreased in the acute phase after starting LFES.Conclusions: We conclude that LFES ameliorates CKD-induced skeletal muscle atrophy by up-regulation of the IGF-1 signaling pathway which improves protein metabolism and promotes myogenesis.The potential mechanisms leading to upregulation of IGF are 1) decrease of microRNA-1 and -206 in the early phase of LEFS resulting in reversal of the inhibition of IGF-1 production by these microRNAs or 2) direct secretion of IGF-1 by M2 macrophages in the later phase inflammatory response.

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