Exercise Counterbalances Rho/ROCK2 Signaling Impairment in the Skeletal Muscle and Ameliorates Insulin Sensitivity in Obese Mice.

Vitor R Muñoz,Ana P A Macêdo,Young-Bum Kim,José Rodrigo Pauli,Dennys E Cintra,Adelino S R Da Silva,Rafael C Gaspar,Eduardo R Ropelle,Matheus B Severino,Fernando M Simabuco

doi:10.3389/fimmu.2021.702025

Abstract

Physical exercise is considered a fundamental strategy in improving insulin sensitivity and glucose uptake in skeletal muscle. However, the molecular mechanisms underlying this regulation, primarily on skeletal muscle glucose uptake, are not fully understood. Recent evidence has shown that Rho-kinase (ROCK) isoforms play a pivotal role in regulating skeletal muscle glucose uptake and systemic glucose homeostasis. The current study evaluated the effect of physical exercise on ROCK2 signaling in skeletal muscle of insulin-resistant obese animals. Physiological (ITT) and molecular analysis (immunoblotting, and RT-qPCR) were performed. The contents of RhoA and ROCK2 protein were decreased in skeletal muscle of obese mice compared to control mice but were restored to normal levels in response to physical exercise. The exercised animals also showed higher phosphorylation of insulin receptor substrate 1 (IRS1 Serine 632/635) and protein kinase B (Akt) in the skeletal muscle. However, phosphatase and tensin homolog (PTEN) and protein-tyrosine phosphatase-1B (PTP-1B), both inhibitory regulators for insulin action, were increased in obesity but decreased after exercise. The impact of ROCK2 action on muscle insulin signaling is further underscored by the fact that impaired IRS1 and Akt phosphorylation caused by palmitate in C2C12 myotubes was entirely restored by ROCK2 overexpression. These results suggest that the exercise-induced upregulation of RhoA-ROCK2 signaling in skeletal muscle is associated with increased systemic insulin sensitivity in obese mice and further implicate that muscle ROCK2 could be a potential target for treating obesity-linked metabolic disorders.

Highlights

The metabolic condition of insulin resistance precedes type 2 diabetes mellitus and has generated a high number of deaths worldwide [1, 2]
Following the obesity and insulin resistance induction period, a set of obese mice began the physical exercise for eight weeks
The physical exercise restored these levels and increased the mRNA levels of Gpi1 and Pfkp (Figure 4B). These results suggest that exercise training has beneficial effects on insulin sensitivity and glucose metabolism by increasing the expression of critical molecules associated with Rho-ROCK2 signaling, which could contribute to increased insulin-sensitizing effects in the skeletal muscle in obese mice (Figure 4C)

Summary

Introduction

The metabolic condition of insulin resistance precedes type 2 diabetes mellitus and has generated a high number of deaths worldwide [1, 2]. In this scenario, considering that the mechanisms related to insulin resistance are not fully understood, it is relevant to investigate new potential regulators of insulin-stimulated glucose uptake in peripheral tissues (e.g., skeletal muscle) [3,4,5,6]. The deficiency of ROCK1 impaired the skeletal muscle insulin signaling and declined the systemic insulin sensitivity [11]. These findings suggested that ROCK1 exerts fundamental action on insulin signaling in skeletal muscle and collaborates notoriously for glycemic homeostasis of the organism

Methods

Results

Discussion

Conclusion