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

Wilson Max Almeida Monteiro De Moraes,Daniel Araki Ribeiro,Alessandra Medeiros,Maria Claudia Irigoyen,Jonato Prestes,Patricia Chakur Brum,Nathalie Alves Da Paixão,Pamella Ramona Moraes De Souza,Andrea G Marshall,Luís Gustavo Oliveira De Sousa

doi:10.1111/jcmm.13374

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.

Highlights

chronic kidney disease (CKD) represents a major health burden for many countries, in part due to its aetiology that is based in highly prevalent diseases such as diabetes and hypertension
5/6Nx model displayed similarities with clinical conditions observed in humans with CKD, showing progressive decline in renal function and reductions in body weight gain
The present research confirmed that these clinical conditions associated with CKD led to disruption of normal skeletal muscle homeostasis, leading to accumulation of misfolded proteins, increased apoptotic markers and oxidative damage

Summary

Introduction

CKD represents a major health burden for many countries, in part due to its aetiology that is based in highly prevalent diseases such as diabetes and hypertension. The endoplasmic reticulum (ER) is the major site in the cell for cellular Ca2+ storage, as well as lipid and protein synthesis, folding, assembly and trafficking. Certain stressful conditions, such as increased synthesis of secretory proteins, oxidative stress and inflammation, disrupt ER homeostasis and lead to the accumulation of misfolded proteins in the ER lumen. To cope with this stress, cells induce the UPR, which either repairs or degrades cytotoxic, damaged proteins using molecular chaperones and proteolytic systems, while attenuating protein translation [10]

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