Aerobic exercise training rescues protein quality control disruption on white skeletal muscle induced by chronic kidney disease in rats

Abstract

We tested whether aerobic exercise training (AET) would modulate the skeletal muscle protein quality control (PQC) in a model of chronic kidney disease (CKD) in rats. Adult Wistar rats were evaluated in four groups: control (CS) or trained (CE), and 5/6 nephrectomy sedentary (5/6NxS) or trained (5/6NxE). Exercised rats were submitted to treadmill exercise (60 min., five times/wk for 2 months). We evaluated motor performance (tolerance to exercise on the treadmill and rotarod), cross‐sectional area (CSA), gene and protein levels related to the unfolded protein response (UPR), protein synthesis/survive and apoptosis signalling, accumulated misfolded proteins, chymotrypsin‐like proteasome activity (UPS activity), redox balance and heat‐shock protein (HSP) levels in the tibialis anterior. 5/6NxS presented a trend towards to atrophy, with a reduction in motor performance, down‐regulation of protein synthesis and up‐regulation of apoptosis signalling; increases in UPS activity, misfolded proteins, GRP78, derlin, HSP27 and HSP70 protein levels, ATF4 and GRP78 genes; and increase in oxidative damage compared to CS group. In 5/6NxE, we observed a restoration in exercise tolerance, accumulated misfolded proteins, UPS activity, protein synthesis/apoptosis signalling, derlin, HSPs protein levels as well as increase in ATF4, GRP78 genes and ATF6α protein levels accompanied by a decrease in oxidative damage and increased catalase and glutathione peroxidase activities. The results suggest a disruption of PQC in white muscle fibres of CKD rats previous to the atrophy. AET can rescue this disruption for the UPR, prevent accumulated misfolded proteins and reduce oxidative damage, HSPs protein levels and exercise tolerance.

Muscle changes with high-intensity aerobic training in an animal model of renal disease

“…HIAT (swimming) improved exercise capacity in trained rats with RD by significantly increasing the maximum load supported during effort at the end of the training period. AT can reduce the effect of uremia on muscle tissue and increase muscle function, consequently improving exercise tolerance 9 .…”

“…The levels of pro-inflammatory cytokines (IL6, TNF-α, and C-reactive protein) are increased in CKD, which stimulate the breakdown of muscle proteins. Moraes et al 9 demonstrated that aerobic exercise attenuated muscle apoptosis via Akt signaling, reduced protein changes, thereby preventing proteotoxicity, and reduced cellular stress induced by chronic uremia.…”

Regular exercise and branched‐chain amino acids prevent ischemic acute kidney injury‐related muscle wasting in mice

“…Ischemic AKI causes distinct damage to organs including the lungs, liver, and intestines (Doi et al., 2014; Golab et al., 2009; Nakazawa et al., 2017; Park et al., 2011). Skeletal myocytes can recognize pathogen‐associated molecules via toll‐like receptors (TLRs) 2 and 4 to initiate an interleukin (IL)‐6 transcriptional response (De Moraes et al., 2018; Frost, Nystrom, & Lang, 2006). Therefore, we induced a 35‐min IRI in the left kidney with an intact right kidney to examine the role of organ crosstalk between damaged kidneys and skeletal muscle under non‐uremic conditions.…”

“…Regular exercise exerts a positive effect on muscle mass in CKD by enhancing protein synthesis and suppressing proteolysis via UPS activation (Bacurau et al., 2016; De Moraes et al., 2018; Sakai et al., 2017; Yoshida et al., 2017). For instance, exercise has been found to increase PGC‐1α mRNA expression, a master regulator of mitochondrial biosynthesis and energy metabolism (Cantó & Auwerx, 2009; Wu et al., 1999).…”

Understanding the Role of Exercise in Nonalcoholic Fatty Liver Disease: ERS-Linked Molecular Pathways

“…If ERS is induced by unfolded or misfolded proteins, it may be triggered by the accumulation of misfolded proteins to a certain threshold. Aerobic exercise can prevent accumulated misfolded proteins and reduce oxidative damage, heat-shock protein levels, and exercise tolerance [ 69 ]. Exercise-induced metabolic stress could activate the UPR, mediating exercise-induced adaptation responses.…”