Chronic kidney disease induces autophagy leading to dysfunction of mitochondria in skeletal muscle

Abstract

Chronic kidney disease (CKD) causes loss of lean body mass by multiple mechanisms. This study examines whether autophagy-mediated proteolysis contributes to CKD-induced muscle wasting. We tested autophagy in the muscle of CKD mice with plantaris muscle overloading to mimic resistance exercise or with acupuncture plus low-frequency electrical stimulation (Acu/LFES) treatment. In CKD muscle, Bnip3, Beclin-1, and LC3II mRNAs and proteins were increased compared with those in control muscle, indicating autophagosome-lysosome formation induction. Acu/LFES suppressed the CKD-induced upregulation of autophagy. However, overloading increased autophagy-related proteins in normal and CKD muscle. Serum from uremic mice induces autophagy formation but did not increase the myosin degradation or actin break down in cultured muscle satellite cells. We examined mitochondrial biogenesis, copy number, and ATP production in cultured myotubes, and found all three aspects to be decreased by uremic serum. Inhibition of autophagy partially reversed this decline in cultured myotubes. In CKD mice, the mitochondrial copy number, biogenesis marker peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), mitochondrial transcription factor A (TFAM), and mitochondrial fusion marker Mitofusin-2 (Mfn2) are decreased. Both muscle overloading and Acu/LFES increased mitochondrial copy number, and reversed the CKD-induced decreases in PGC-1α, TFAM, and Mfn2. We conclude that the autophagy is activated in the muscle of CKD mice. However, myofibrillar protein is not directly broken down through autophagy. Instead, CKD-induced upregulation of autophagy leads to dysfunction of mitochondria and decrease of ATP production.

Reductions in skeletal muscle mitochondrial mass are not restored following exercise training in patients with chronic kidney disease

“…D, Densitometry analysis of OXPHOS complex abundance. 28,55,56 In line with previous results from animal models of CKD, 26,28 we have shown that patients with moderate to severe CKD stage 3b-5 display a 46% reduction in skeletal muscle CS activity and a 86% decrease in the porin/β-actin ratio suggesting a substantial reduction in mitochondrial mass compared to healthy matched controls. E, Representative western blot analysis of OXPHOS protein complexes in healthy controls and CKD patients ageing and also in other disease states.…”

“…C, Representative western blot of porin/β-actin ratio in healthy controls and CKD patients. These studies have reported a reduction in complex IV enzyme activity and mitochondrial respiratory capacity, 26 a reduction in mitochondrial mass, [26][27][28] an increase in mitophagy, 28,55 and a reduction in PGC-1α mRNA expression. ***Denotes P < .001 vs healthy controls, *P < .05 vs healthy controls.…”

“…Traditionally, AE training is well documented to stimulate mitochondrial biogenesis, driven by energy stresses created during the exercise bout 38 and resulting in increased exercise capacity and tolerance. 55 Finally, exercise-mediated improvements in CS activity were reported to be reduced in uraemic rats. 57 Furthermore, 8 weeks of CE in older adults resulted in greater improvements in mitochondrial OXPHOS and biogenesis markers than either intervention alone.…”

Svak kobling mellom kronisk utmattelsessyndrom og pyruvat dehydrogenasemangel

“…For example, the study shows reduced production of high-energy phosphates (ATP) in vitro. In a mouse model in which cultivated muscle cells are exposed to serum from individuals with muscular atrophy and chronic renal failure, ATP production is also reduced (11).…”

Inhibition of microRNA-376b Protects Against Renal Interstitial Fibrosis via Inducing Macrophage Autophagy by Upregulating Atg5 in Mice with Chronic Kidney Disease

“…Increased ROS production can reflect the degree of oxidative stress, which is a contributor to CKD development [35]. LC3, which is composed of LC3-I and LC3-II, is a critical marker of autophagy, and LC3 II/I represents the activation of autophagy at the initial stage [36]. In fact, an elevated LC3 II/I ratio represents enhanced autophagy, and Beclin-1 is not only associated with autophagy but also with resistance to apoptosis [37].…”