Excessive exercise elicits poly (ADP-ribose) Polymerase-1 activation and global protein PARylation driving muscle dysfunction and performance impairment

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Crisol, Barbara M. ; Rocha, Matheus B. ; Franco, Beatriz ; Morelli, Ana Paula ; Katashima, Carlos K. ; Junior, Scylas J. A. ; Carneiro, Fernanda S. ; Braga, Renata R. ; de Azambuja, Graciana ; Costa, Raul Gobato ; Esteves, Andrea M. ; Mori, Marcelo A. ; Oliveira, Maria C. G. ; Cintra, Dennys E. ; Pauli, Jose R. ; Larsen, Filip J. ; Silva, Adelino S. R. da ; Ropelle, Eduardo R.

• Tipo de documento: Artigo Científico
• Fonte: MOLECULAR METABOLISM; v. 96, p. 15-pg., 2025-06-01.

Resumo

Excessive exercise combined with inadequate recovery time may trigger fatigue, performance impairment, and ultimately the overtraining syndrome. The intramyocellular mechanisms involved in the overtraining syndrome remain only partially known. Here, we combined multi-omics analyses from isogenic BXD mouse strains with a mouse model of overtraining and excessive exercise protocol in mice and humans to evaluate the molecular mechanism involved in the performance impairment induced by excessive exercise. We identified that BXD mouse strains with elevated levels of Parp1 gene expression in the skeletal muscle displayed features like overtraining syndrome and abnormal muscle genetic signature. High PARP1 protein content and aberrant PARylation of proteins were detected in the skeletal muscle of overtrained, but not in trained mice. Overtraining syndrome reduced mitochondrial function promoted by exercise training, induced muscle hyperalgesia, reduced muscle fiber size and promoted a similar gene signature of myopathy and atrophy models. Short periods of excessive exercise also increased PARylation in the skeletal muscle of mice and healthy subjects. The pharmacological inhibition of PARP1, using Olaparib, and genetic Parp1 ablation, preserved muscle fiber morphology and protected against physical performance impairment and other symptoms of the overtraining syndrome in mice. In conclusion, PARP1 excessive activation is related to muscle abnormalities led by long or short periods of excessive exercise, and here we suggest that PARP1 is a potential target in the treatment and prevention of overtraining syndrome. (c) 2025 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/). (AU)

• Processo FAPESP: 18/04192-5 - Avaliação da Parilação e do Desequilíbrio Mitonuclear e da UPRmt na Musculatura Esquelética de Camundongos em Overtraining.
• Beneficiário: Barbara Moreira Crisol
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 19/21709-4 - Implicações do desequilíbrio mitonuclear e da UPRmt em neurônios hipotalâmicos na gênese da Obesidade
• Beneficiário: Eduardo Rochete Ropelle
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 22/08930-6 - A via interleucina-6/quinurenina no hipocampo e sua relação com inflamação, apoptose e distúrbios cognitivos e comportamentais na condição de excesso de exercício físico em camundongos
• Beneficiário: José Rodrigo Pauli
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 21/08354-2 - A ação recíproca do sistema imune e do metabolismo como principal determinante do processo de envelhecimento
• Beneficiário: Marcelo Alves da Silva Mori
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 19/22512-0 - Efeitos da restrição calórica e do exercício físico sobre o mecanismo de agregação proteica no músculo esquelético
• Beneficiário: Barbara Moreira Crisol
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
• Processo FAPESP: 13/07607-8 - CMPO - Centro Multidisciplinar de Pesquisa em Obesidade e Doenças Associadas
• Beneficiário: Licio Augusto Velloso
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs