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

Author(s):Show less -

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.

• Document type: Journal article
• Source: MOLECULAR METABOLISM; v. 96, p. 15-pg., 2025-06-01.

Abstract

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)

• FAPESP's process: 18/04192-5 - Evaluation of the Parilation and the Mitonuclear Imbalance and the UPRmt in the Skeletal Musculature of Mice in Overtraining.
• Grantee: Barbara Moreira Crisol
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 19/21709-4 - Implications of mitonuclear imbalance and UPRmt in hypothalamic neurons in the genesis of Obesity
• Grantee: Eduardo Rochete Ropelle
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 22/08930-6 - The interleukin-6/kynurenine pathway in the hippocampus and its relationship with inflammation, apoptosis, and cognitive and behavioral disorders in excessive exercise condition in mice
• Grantee: José Rodrigo Pauli
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/08354-2 - The interplay between the immune system and metabolism as a key determinant of the aging process
• Grantee: Marcelo Alves da Silva Mori
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 19/22512-0 - Effects of calorie restriction and exercise in the skeletal muscle protein aggregration
• Grantee: Barbara Moreira Crisol
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center
• Grantee: Licio Augusto Velloso
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC