Incremental load training improves renal fibrosis by regulating the TGF‑β1/TAK1/MKK3/p38MAPK signaling pathway and inducing the activation of autophagy in aged mice

Abstract

Recent studies have confirmed that kidney tissue fibrosis is closely linked to the natural aging of organs. One of its major characteristics is the reduction of autophagic activity. However, to date, few studies have assessed whether incremental load training is able to improve the occurrence of renal fibrosis caused by natural aging and the underlying mechanisms. In the present study involving male C57/BL mice, an elderly exercise group (OY group) was subjected to progressive load-increasing rotary-bar training (5 days/week, lasting for 6 weeks), with an elderly control group (OC group) and a young control group (YC group) used as controls. Renal fibrosis and autophagy-associated indicators were assessed by Masson's staining, reverse transcription-quantitative PCR analysis, western blotting, immunofluorescence and transmission electron microscopy. The results suggested that collagen deposition in the basal part of the renal tubular epithelium and glomeruli in the OY group was significantly lower than that in the OC group. In the OC group, the protein expression levels of E-cadherin, Beclin 1 and light chain 3 were significantly decreased, and increases in α-smooth muscle actin-positive signals were observed in the glomerular matrix and renal capsule wall. Furthermore, the expression of transforming growth factor (TGF)-β1 and its downstream signaling molecules TGF-β-activated kinase 1 (TAK1), mitogen-activated protein kinase (MAPK) kinase (MKK3) and p38MAPK were downregulated following training. The present study confirmed that incremental load training may improve renal fibrosis in aged mice by regulating the TGF-β1/TAK1/MMK3/p38MAPK signaling pathway and inducing the activation of autophagy to reduce the synthesis of extracellular matrix and delay the epithelial-mesenchymal transition. The present study provides a novel experimental basis for the intervention of incremental load training to prevent senile renal fibrosis.

RIPK3: A New Player in Renal Fibrosis

“…TGF-β-activated kinase 1 (TAK1), interacts with TGF-β1 and contributes to the development and progression of organ fibrosis through TGF-β1/TAK1/MKK3/p38MAPK, TGF-β1/TAK1/MKK4/JNK, and TGF-β1/TAK1/ NFκB pathways (Kim and Choi, 2012;Biesemann et al, 2015;Li et al, 2017;Wu et al, 2017;Zhou et al, 2018;Bao et al, 2019). Few studies of TAK1 on necroptosis have been reported, and these mostly report on RIPK1-dependent cell death.…”

A Handful of Details to Ensure the Experimental Reproducibility on the FORCED Running Wheel in Rodents: A Systematic Review

“…The implementation of a load progression (intensity, volume, and density of the exercise) during the training program is one of the main training principles ( 164 ). A load progression protocol ensures that new adaptations are occurring in the body throughout the weeks of training ( 165 ). Therefore, a failure to implement a load progression protocol might produce misinterpretations of the exercise effects.…”

Targeting fibrosis in the Duchenne Muscular Dystrophy mice model: an uphill battle

“…The TGFb-TAK1 pathway is a shared molecular pathway regulating TyrK, BRD and p38 MAPK signaling. Growing evidence supports the role of TAK1 as a significant regulator of TGFb signaling through the regulation of the profibrotic response in several systems [43][44][45][83][84][85][86][87]. Very recently, it has been shown that the action of Catalpol (an anti-inflammatory and antioxidant drug from Chinese medicinal herb Rehmannia) on DMD histopathology was due to its binding to TAK1 [88,89].…”