Targeting nuclear receptor NR2F6 : Effect on skeletal muscle thermogenesis.

• Grant number: 23/18209-5
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: September 01, 2024
• End date: February 29, 2028
• Field of knowledge: Biological Sciences - Morphology
• Principal Investigator: Leonardo dos Reis Silveira
• Grantee: Michelle Gomes da Silva
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

The RNA-seq transcriptional analysis in NR2F6 knocked-down cells revealed that genes associated with metabolic process including cellular differentiation, muscle contraction, and Ca2+ transport were markedly upregulated underscoring the role of NR2F6 on cellular metabolism. A number of studies have demonstrated that skeletal muscle increases heat production by uncoupling of Serca ATP hydrolysis from Ca2+ transport, clearly suggesting a role of NR2F6 in the muscle thermogenic process. Consistent with the thermogenesis activity in skeletal muscle, knockdown of NR2F6 markedly induced the AMPK phosphorylation, an effect that was reflected in increased insulin response. In addition, genes associated with thermogenic process in skeletal muscle including SLC25A4 (ATP/ADP carrier) and ATP1A1 (ATPase Na+/k+ transporting) and ryanodine receptor (Ryr1) were also upregulated in NR2F6 knockdown cells. We also found NR2F6 responsive elements at DNA regulatory sequences of Ca2+ transport genes including Sln, ATP2A1 (Serca1A), ATP2A2 (Serca2A), and Ryr1. Likewise, the NR2F6 responsive element was also found in the DNA regulatory sequence of PPARGC1±, an important player of the thermogenesis process in brown adipocytes and skeletal muscle cells. Together this finding suggests that the nuclear receptor, NR2F6 , might be an important regulator of mitochondrial function and thermogenic process in skeletal muscle.