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목종수Jongsoo Mok

서울대학교

Proc. Natl. Acad. Sci. USA, Jan 23 2024, 121 (4) | https://doi.org/10.1073/pnas.2308960121 PROKR1-CREB-NR4A2 axis for oxidative muscle fiber specification and improvement of metabolic function

Jongsoo Mok^a, Jeong Hwan Park^b, Su Chong Yeom^a,b, and Joonghoon Park^a,b,1

^aInstitute of Green Bio Science and Technology, Seoul National University, Pyeongchang, Republic of Korea, 25354; and

^bDepartment of International Agricultural Technology, Graduate School of International Agricultural Technology, Pyeongchang, Seoul National University, Republic of Korea, 25354

¹To whom correspondence may be addressed. : Joonghoon Park

Abstract

Metabolic disorders are characterized by an imbalance in muscle fiber composition, and a potential therapeutic approach involves increasing the proportion of oxidative muscle fibers. Prokineticin receptor 1 (PROKR1) is a G protein-coupled receptor that plays a role in various metabolic functions, but its specific involvement in oxidative fiber specification is not fully understood. Here, we investigated the functions of PROKR1 in muscle development to address metabolic disorders and muscular diseases. A meta-analysis revealed that the activation of PROKR1 upregulated exercise-responsive genes, particularly nuclear receptor subfamily 4 group A member 2 (NR4A2). Further investigations using ChIP-PCR, luciferase assays, and pharmacological interventions demonstrated that PROKR1 signaling enhanced NR4A2 expression by Gs-mediated phosphorylation of cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) in both mouse and human myotubes. Genetic and pharmacological interventions showed that the PROKR1-NR4A2 axis promotes the specification of oxidative muscle fibers in both myocytes by promoting mitochondrial biogenesis and metabolic function. Prokr1-deficient mice displayed unfavorable metabolic phenotypes, such as lower lean mass, enlarged muscle fibers, impaired glucose, and insulin tolerance. These mice also exhibited reduced energy expenditure and exercise performance. The deletion of Prokr1 resulted in decreased oxidative muscle fiber composition and reduced activity in the Prokr1-CREB-Nr4a2 pathway, which were restored by AAV-mediated Prokr1 rescue. In summary, our findings highlight the activation of the PROKR1-CREB-NR4A2 axis as a mechanism for increasing the oxidative muscle fiber composition, which positively impacts overall metabolic function. This study lays an important scientific foundation for the development of effective muscular-metabolic therapeutics with unique mechanisms of action.

논문정보

형식Research article
게재일2024년 01월 (BRIC 등록일 2024-01-18)
연구진국내 연구진
분야 생명과학 > 세포생물학

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