Low-frequency electrical stimulation attenuates muscle atrophy in CKD--a potential treatment strategy.

Abstract

Effective therapeutic strategies to treat CKD-induced muscle atrophy are urgently needed. Low-frequency electrical stimulation (LFES) may be effective in preventing muscle atrophy, because LFES is an acupuncture technique that mimics resistance exercise by inducing muscle contraction. To test this hypothesis, we treated 5/6-nephrectomized mice (CKD mice) and control mice with LFES for 15 days. LFES prevented soleus and extensor digitorum longus muscle weight loss and loss of hind-limb muscle grip in CKD mice. LFES countered the CKD-induced decline in the IGF-1 signaling pathway and led to increases in markers of protein synthesis and myogenesis and improvement in muscle protein metabolism. In control mice, we observed an acute response phase immediately after LFES, during which the expression of inflammatory cytokines (IFN-γ and IL-6) increased. Expression of the M1 macrophage marker IL-1β also increased acutely, but expression of the M2 marker arginase-1 increased 2 days after initiation of LFES, paralleling the change in IGF-1. In muscle cross-sections of LFES-treated mice, arginase-1 colocalized with IGF-1. Additionally, expression of microRNA-1 and -206, which inhibits IGF-1 translation, decreased in the acute response phase after LFES and increased at a later phase. We conclude that LFES ameliorates CKD-induced skeletal muscle atrophy by upregulation of the IGF-1 signaling pathway, which improves protein metabolism and promotes myogenesis. The upregulation of IGF-1 may be mediated by decreased expression of microRNA-1 and -206 and/or activation of M2 macrophages.