Scholarship 23/16626-8 - Autofagia, Exercício físico - BV FAPESP
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Modulation of Rev-erb-alpha by global deletion of NLRP3.

Grant number: 23/16626-8
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Start date until: April 01, 2024
End date until: March 31, 2026
Field of knowledge:Health Sciences - Physical Education
Principal Investigator:Adelino Sanchez Ramos da Silva
Grantee:Eliezer Lucas Pires Ramos
Host Institution: Escola de Educação Física e Esporte de Ribeirão Preto (EEFERP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:19/11820-5 - Nr1d1 function on the aging-associated Sarcopenia, AP.TEM

Abstract

According to the literature, the absence of the pyrin domain of the NLR family (NLRP3) is related to muscle aging and the progression of sarcopenia (1). The NLRP3 inflammasome can be induced by several pathogens and molecular patterns associated with cellular damage and damaged organelles, and its activation stimulates the maturation of pro-inflammatory cytokines, such as interleukin-1² (2). NLRP3 is closely related to aging, formation of reactive oxygen species (ROS), muscle and mitochondrial dysfunction (2). Elegantly, McBride and colleagues (3) demonstrated that NLRP3 participates in the age-related loss of muscle glycolytic potential. Sayed and collaborators (1) observed that NLRP3 knockout females showed a reduction in lactate, number of muscle fibers and mitochondrial number at 12 months of age. At 24 months, mitochondrial damage, reduced locomotor activity, destruction of mitochondrial cristae, fragmentation were detected. nuclear, formation of tubular aggregates and increased fragility index. Studies on the set of physiological processes in cells are extremely necessary, since several pathways have cellular communication and may be directly related to sarcopenia, such as autophagy (4), mitochondrial biogenesis (5) and protein synthesis (6). Knowing that with aging there is a decrease in the autophagic process, since investigations into the relationship between autophagy and NLRP3 in skeletal muscle are limited, the first objective of the current project will be to verify whether sarcopenia, due to the absence of NLRP3 (NLRP3 mice knockout/KO), occurs due to impairment in the autophagy pathway. Knowing that physical exercise is associated with increased autophagy, as a second objective, we will verify the role of NLRP3 in the response of the autophagy pathway in the skeletal muscle of mice after a combined exercise protocol. The Rev-erb± protein, encoded by the nuclear receptor subfamily 1 group D member 1 (Nr1d1) gene, is an important physiological regulator of autophagy,mitochondrial content, oxidative function and maintenance of skeletal muscle mass, making this protein a promising molecular target for the prevention and treatment of sarcopenia. FewStudies have emphasized the role of Rev-erb± in skeletal muscle, in addition to which proteins and molecular pathways Rev-erb± is capable of modulating (7, 8). According to our preliminary dataUsing bioinformatics analysis, the Rev-erb± protein may be associated with other cellular and molecular events not yet investigated in skeletal muscle. Based on this information, and to expand knowledge about the behavior of the Nr1d1 gene and its Rev-erb± protein in different aging models, the third objective of this project will be to verify whether the global deletion of NLRP3 can modulate the Rev-erb± molecular pathway. in skeletal muscle. Furthermore, the present research project will investigate the relationship between NLRP3 and Rev-erb± in C2C12 cells (myoblasts/myotubes) in vitro.

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