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Functions and regulatory mechanisms of lincRNA-p21 in skeletal muscle: role on stem cell fate, myogenesis, trophism, contractility, exercise performance and injury repair

Abstract

Skeletal muscle is the most abundant organ with vital functions in the body. Myoblast proliferation and differentiation are key steps during skeletal muscle development, as well as contributing to muscle regeneration and growth in adults. On the other hand, alterations in myogenesis may be involved in many muscle disorders, in which alterations in regenerative capacity play a crucial role in disease progression. Therefore, the identification of new components that control these processes can contribute to the understanding of muscle development mechanisms and potentially allow the identification of new therapeutic targets. The discovery that 98% of the human genome, although transcribed, does not encode proteins was crucial in recognizing the role of long non-coding RNAs (lncRNAs) as critical regulators of cellular function at the epigenetic, transcriptional, and post-transcriptional levels. Although studies indicate that lncRNAs play key roles in tissue structure and function, their role on myogenic, muscle mass control, and muscle regeneration regulation remains poorly understood. Furthermore, abnormalities of lncRNAs have been directly linked to skeletal muscle biology and disease. LincRNA-p21 is involved in several cellular processes via regulation of the expression of multiple target genes; however, its expression and effects on skeletal muscle are unknown. Therefore, the main objective of this study is to investigate the impact of lincRNA-p21 deletion on skeletal muscle myogenic, phenotypic, functional, reparative, and molecular adaptations, and to provide additional knowledge on how transcriptional and post-transcriptional processes are integrated to orchestrate these muscle changes. For the first stage of the study, we will evaluate the effects of lincRNA-p21 inhibition on muscle myogenesis, morphology, and metabolism in vitro using C2C12 and primary cells from lincRNA-p21 knockout mice. In the second stage of the study, we will evaluate the effects of lincRNA-p21 inhibition on phenotypic characterization in vivo in lincRNA-p21 knockout mice. In the third step, we will evaluate the effects of lincRNA-p21 inhibition on muscle function and repair capacity in vivo, as well as its effects on physical performance. Then, the molecular characterization in skeletal muscle of lincRNA-p21 knockout mice will be analyzed in order to evaluate genes and signaling pathways related to structural and functional alterations found. In addition, we will evaluate the recovery of muscle phenotype via gene therapy using AAV9 delivery in animals with lincRNA-p21 deletion. Finally, we will investigate the expression of muscle lincRNA-p21 both in models induced by physiological stimuli such as physical training and pathological in animals with muscular dystrophy, cancer, and heart failure. Thus, the study of lincRNA-p21 may lead to the identification of molecular circuits that are controlled by RNAs (lncRNA-miRNA-mRNA network) during the skeletal muscle differentiation process and that, when deregulated, lead to pathological events. These findings will provide insights that can assist in understanding many basic concepts of the molecular mechanisms involved in skeletal muscle homeostasis and in developing new therapeutic interventions for muscle diseases. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
TRETTEL, CAIO DOS SANTOS; PELOZIN, BRUNO ROCHA DE AVILA; BARROS, MARCELO PAES; BACHI, ANDRE LUIS LACERDA; BRAGA, PEDRO GABRIEL SENGER; MOMESSO, CESAR MIGUEL; FURTADO, GUILHERME EUSTAQUIO; VALENTE, PEDRO AFONSO; OLIVEIRA, EDILAMAR MENEZES; HOGERVORST, EEF; et al. Irisin: An anti-inflammatory exerkine in aging and redox-mediated comorbidities. FRONTIERS IN ENDOCRINOLOGY, v. 14, p. 9-pg., . (17/06032-2, 15/17275-8, 22/03138-2)
DA SILVA JR, NATAN D. D.; ANDRADE-LIMA, ALUISIO; CHEHUEN, MARCEL R. R.; LEICHT, ANTHONY S. S.; BRUM, PATRICIA C. C.; OLIVEIRA, EDILAMAR M. M.; WOLOSKER, NELSON; PELOZIN, BRUNO R. A.; FERNANDES, TIAGO; FORJAZ, CLAUDIA L. M.. Walking Training Increases microRNA-126 Expression and Muscle Capillarization in Patients with Peripheral Artery Disease. GENES, v. 14, n. 1, p. 9-pg., . (15/13800-0, 22/03138-2)

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