Rev-erbalpha and insulin resistance in skeletal muscle: a USP-Harvard collaborative investigation

• Grant number: 25/11589-2
• Support Opportunities: Regular Research Grants
• Start date: November 01, 2025
• End date: October 31, 2026
• Field of knowledge: Health Sciences - Physical Education
• Mobility Program: SPRINT - Projetos de pesquisa - Mobilidade
• Principal Investigator: Adelino Sanchez Ramos da Silva
• Grantee: Adelino Sanchez Ramos da Silva
• Principal researcher abroad: Carl Ronald Kahn
• Institution abroad: Harvard University, Boston , United States
• Host Institution: Escola de Educação Física e Esporte de Ribeirão Preto (EEFERP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• City of the host institution: Ribeirão Preto
• Associated research grant: 19/11820-5 - Nr1d1 function on the aging-associated Sarcopenia, AP.TEM

Abstract

Insulin resistance in skeletal muscle (SM) is a key feature of type 2 diabetes (T2D) and a major contributor to impaired glucose homeostasis. Recent findings from our group suggest that the nuclear receptor Rev-Erb¿ (encoded by Nr1d1), a circadian clock component, is pivotal in regulating insulin signaling pathways in SM. Using CRISPR/Cas9-edited Rev-Erb¿ knockout myoblasts and pharmacological activation with SR9009, we identified significant alterations in insulin signaling and glucose uptake, highlighting Rev-Erb¿ as a promising molecular target for metabolic intervention. These discoveries, developed under a FAPESP-funded Thematic Project (19/11820-5), established a collaborative link with Dr. Carl Ronald Kahn (Harvard Medical School), which was further strengthened by a BEPE internship (22/05957-0) and a scientific mission by Prof. Adelino. In the proposed exchange, Prof. Adelino and Dr. Vitor Rosetto Muñoz will return to the Joslin Diabetes Center for a 7-day visit in 2026 to perform pilot experiments using iPSC-derived myoblasts from healthy and T2D donors. This collaboration will support the ongoing Thematic Project submission (24/20524-9), promote data integration using human cellular models, and facilitate future joint proposals to advance translational research in obesity and T2D. (AU)