Abstract
Chronic kidney disease (CKD) causes several systemic changes, including muscular homeostasis, and eventually results in muscle atrophy. CKD-induced muscle atrophy is highly prevalent, and exercise is well known to enhance muscle function in these cases, although the exact mechanism remains unclear. Here, we aim to assess whether the protective effect of aerobic exercise in 5/6 nephrectomized (CKD) mice is associated with mitochondrial dysfunction, autophagy, or inflammation. C57BL/6J mice were randomly allocated into 3 different experimental groups: Sham, CKD, and CKD+aerobic exercise (CKD+AE). Renal function was assessed via serum creatinine and urea levels, and histological PAS and Masson staining were performed. Muscle wasting was determined based on grip strength, cross-sectional area (CSA), and MyHC protein expression. We also measured mitochondrial dysfunction in mice by assessing mtDNA, ROS, ATP production, and mitochondrial configuration. Autophagy was determined via assessments for Atg7, LC3, and SQSTM1 on western blotting. Inflammation was identified via proinflammatory cytokines and NLRP3 inflammasome components using real-time PCR and western blotting. We found that CKD mice exhibited higher BUN and creatinine levels and more severe glomerulosclerosis in the glomeruli and renal tubulointerstitial fibrosis, relative to the Sham group; all these effects were relieved by aerobic exercise. Moreover, grip strength, CSA, and MyHC protein expression were improved after 8 weeks of aerobic exercise. Furthermore, aerobic exercise significantly decreased MDA levels, increased SOD2 activity and ATP production, and improved mitochondrial configuration, relative to the CKD group. In addition, aerobic exercise downregulated the overexpression of proinflammatory cytokines and NLRP3 inflammasome components and balanced the mitochondrial biogenesis and autophagy-lysosomal system. Thus, we observed that aerobic exercise may ameliorate CKD-induced muscle wasting by improving mitochondrial dysfunction, inflammation, and autophagy-lysosomal system in uremic cachexia.
Highlights
Chronic kidney disease (CKD) is a complicated progressive disease that results in the progressive and irreversible loss of renal function and has become an increasingly important public health issue worldwide [1, 2]
We found that factors such as mitochondrial dysfunction, inflammation, and autophagy played a very critical role in CKD-induced muscle wasting
Aerobic exercise may attenuate the loss of muscle mass in CKD mice by enhancing grip strength and muscle cross-sectional area (CSA) through the regulation of mitochondrial dysfunction, inflammation, and autophagy
Summary
Chronic kidney disease (CKD) is a complicated progressive disease that results in the progressive and irreversible loss of renal function and has become an increasingly important public health issue worldwide [1, 2]. CKD leads to a reduction in physical function during the initial stages, which gradually worsens as the disease progresses. Physical inactivity is primarily caused by skeletal muscle atrophy. A better understanding of the pathways that cause muscle wasting in CKD is vital to design appropriate therapeutic approaches to limit muscle protein loss. Studies on the related mechanisms specific to CKD remain scarce. Several molecular mechanisms have been proposed to explain CKD-induced skeletal muscle atrophy, including oxidative stress injury or the upregulation of cyclic AMP and growth hormone/insulin-like growth factor 1 [3,4,5]. We aim to determine the pathways causing muscle atrophy in this condition
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