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

Author(s)

Munoz, Vitor R. ^[1] ; Gaspar, Rafael C. ^[1] ; Severino, Matheus B. ^[2] ; Macedo, Ana P. A. ^[1] ; Simabuco, Fernando M. ^[2] ; Ropelle, Eduardo R. ^[1] ; Cintra, Dennys E. ^[3] ; da Silva, Adelino S. R. ^{[4, 5]} ; Kim, Young-Bum ^{[6, 7]} ; Pauli, Jose Rodrigo ^[1]

Affiliation

^[1] Univ Campinas UNICAMP, Lab Mol Biol Exercise, Limeira - Brazil

^[2] Univ Estadual Campinas, Sch Appl Sci, Multidisciplinary Lab Food & Hlth, Limeira - Brazil

^[3] Univ Campinas UNICAMP, Lab Nutr Genom, Limeira - Brazil

^[4] Univ Sao Paulo, Sch Phys Educ & Sport Ribeirao Preto, Ribeirao Preto - Brazil

^[5] Univ Sao Paulo, Ribeirao Preto Med Sch, Postgrad Program Rehabil & Funct Performance, Ribeirao Preto - Brazil

^[6] Harvard Med Sch, Boston, MA 02115 - USA

^[7] Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02215 - USA

• Document type: Journal article
• Source: FRONTIERS IN IMMUNOLOGY; v. 12, JUN 21 2021.
• Web of Science Citations: 0

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. (AU)

• FAPESP's process: 16/18488-8 - The role of physical exercise on molecular pathways of glucose uptake in GLUT-4 knockout mice
• Grantee: José Rodrigo Pauli
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/21491-2 - Role of physical exercise in regulation of rock protein and the effects on insulin signaling in skeletal muscle and liver in obese mice
• Grantee: José Rodrigo Pauli
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/26000-2 - The role of Rock protein on glucose uptake in the skeletal muscle of exercised rodents during the aging process
• Grantee: Vitor Rosetto Muñoz
• Support Opportunities: Scholarships in Brazil - Master