Role of beta2-adrenergic receptor subpopulations on distinct response of slow and fast-twitch muscles under sympathetic hyperactivity

• Grant number: 18/24800-0
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Start date: January 28, 2019
• End date: July 27, 2019
• Field of knowledge: Health Sciences - Physical Education
• Principal Investigator: Patricia Chakur Brum
• Grantee: Janaina da Silva Vieira
• Supervisor: Yang Kevin Xiang
• Host Institution: Escola de Educação Física e Esporte (EEFE). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of California, Davis (UC Davis), United States
• Associated to the scholarship: 16/24284-6 - Role of aerobic physical training in muscle plasticity in experimental model of heart failure induced by pulmonary hypertension, BP.MS

Abstract

Sympathetic hyperactivity (SH) is a hallmark of heart failure (HF) and several lines of evidence suggest that SH contributes to HF induced skeletal myopathy. The latter is characterized by skeletal muscle abnormalities in HF, such as impaired muscle oxidative metabolism atrophy and shift toward fast twitch fibers (type II fibers) that are also more susceptible to atrophic stimuli. Taking into consideration that ²2-adrenoceptors (²2-AR) mediate the activity of sympathetic nervous system in skeletal muscle, little is known about the relative contribution of ²2-AR to muscle atrophy in HF in muscles comprised with different fiber types. ²2AR signaling transduction is modulated by phosphorylation by either GRKs or PKA, which affects receptor trafficking and sensitivity. Of interest, GRKs and PKA selectively label two distinct subpopulations of ²2AR that are spatially segregated on the plasma membrane and undergo distinct membrane trafficking. In a setting of HF and SH, GRKs are increased in heart muscle contributing to ²2AR-dessensitization and endocytosis, however no data is provided about GRK levels in skeletal muscle under SH. Interestingly, in skeletal muscle, GRK levels are higher in fast-twitch fibers than slow-twitch ones, and specific skeletal muscle GRK2 knockout mice affects white glycolytic muscle (extensor digitorum longus) specific force production but not red (soleus) oxidative ones. Thus, the aim of the present study is to investigate the relative contribution of ²2AR signaling for the atrophy associated with SH in skeletal muscles comprised with different fiber types and metabolism (oxidative vs glycolytic fibers). (AU)