Autophagosome‐proteolysis contribute to CKD‐induced muscle atrophy

Autophagy‐lysosome system was reportedly activated in muscle cells during catabolic conditions. we hypothesized that proteolysis through autophagosomes may participate in CKD‐induced muscle protein catabolism. Thus, we examined whether autophagosome activity contributes to CKD‐induced muscle atrophy, and if exercise ameliorates CKD muscle wasting by attenuating autophagosome activity. We induced CKD by subtotal nephrectomy and examined the effect of resistant exercise (i.e., overloading of hindlimb plantaris muscles by removing gastrocnemius and soleus muscles) on muscle atrophy. In isolated plantaris muscles, 4 mRNAs were evaluated as markers of the autophagy‐lysosomal proteolysis pathway. The markers were: 1) microtubule‐associated protein 1A/1B‐light chain 3 II (LC3 II, indicates autophagosome number); 2) BCL2/adenovirus E1B 19 kDa protein‐interacting protein 3 (BNIP3, indexes autophagosome formation); 3) Vps34 (class III PI 3‐kinase, a regulator of autophagic sequestration); and 4) P62 (induction of reduced autophagosome clearance). CKD increased the expression of the mRNAs of the 4 markers (P<0.05) and exercise reversed this, returning to levels measured in control mice. Protein levels of Bnip3, LC3‐II and Beclin‐1 (an upstream regulator of autophagic sequestration) were increased in muscles from CKD mice vs controls. Exercise reversed these increases in autophagosome protein markers. We conclude that autophagosome‐mediated proteolysis contributes to CKD‐induced muscle atrophy. Exercise slows the development of muscle atrophy by up‐regulating the IGF‐1 signaling pathway in part by inhibiting autophagy‐lysosomal proteolysis pathway in CKD. Source of funding: NIH grants, R01 AR060268, R37 DK037571