PUBLICATION
Aerobic exercise ameliorates skeletal muscle atrophy in atic knockout zebrafish through the oxidative phosphorylation pathway
- Authors
- Peng, Z., Yang, T., Xu, S., Yang, B., Zhang, Z., Ding, M., Gu, W., Zheng, L.
- ID
- ZDB-PUB-250708-3
- Date
- 2025
- Source
- Free radical biology & medicine : (Journal)
- Registered Authors
- Keywords
- ATIC, CRISPR-Cas9, aerobic exercise, muscle, oxidative phosphorylation pathway
- MeSH Terms
-
- Aminoimidazole Carboxamide/analogs & derivatives
- Aminoimidazole Carboxamide/metabolism
- Animals
- CRISPR-Cas Systems
- Gene Knockout Techniques
- Hydroxymethyl and Formyl Transferases*/genetics
- Hydroxymethyl and Formyl Transferases*/metabolism
- Mice
- Mitochondria/metabolism
- Multienzyme Complexes
- Muscle, Skeletal*/metabolism
- Muscle, Skeletal*/pathology
- Muscular Atrophy*/genetics
- Muscular Atrophy*/metabolism
- Muscular Atrophy*/pathology
- Muscular Atrophy*/therapy
- Nucleotide Deaminases*/genetics
- Nucleotide Deaminases*/metabolism
- Oxidative Phosphorylation
- Physical Conditioning, Animal*
- Purines/metabolism
- Reactive Oxygen Species/metabolism
- Ribonucleotides/metabolism
- Zebrafish/genetics
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- PubMed
- 40623538 Full text @ Free Radic. Biol. Med.
Citation
Peng, Z., Yang, T., Xu, S., Yang, B., Zhang, Z., Ding, M., Gu, W., Zheng, L. (2025) Aerobic exercise ameliorates skeletal muscle atrophy in atic knockout zebrafish through the oxidative phosphorylation pathway. Free radical biology & medicine. :.
Abstract
The mechanisms linking purine metabolism disorders to skeletal muscle pathology are unclear. This study constructed a CRISPR/Cas9-mediated zebrafish atic knockout model and a siRNA-interfered C2C12 myoblast cell model. We revealed a novel mechanism by which ATIC (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase) deletion drove the atrophy of skeletal muscle through the downregulation of the oxidative phosphorylation of mitochondria (OXPHOS) pathway. It was found that atic/Atic knockout/knockdown led to the interruption of purine de novo synthesis, abnormal 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) accumulation, and blockage of inosine monophosphate (IMP) synthesis, which in turn triggered mitochondrial structural damage, dysfunction of complex I-V function, and a burst of reactive oxygen species (ROS), and ultimately triggered muscle atrophy through activation of the ubiquitin-proteasome system. The progressive aerobic intervention revealed that 8 weeks of training significantly restored skeletal muscle function in zebrafish atic-/- mutants, and the mechanism was related to the enhancement of mitochondrial biogenesis, up-regulation of the core complex expression of the OXPHOS pathway, and the improvement of ROS scavenging ability. These findings reveal that ATIC deficiency disrupts mitochondrial function through purine metabolism dysregulation, linking aberrant AICAR accumulation to OXPHOS impairment, which provides a theoretical basis for the early warning of muscular toxicity of targeted purine metabolizing drugs and lays a molecular foundation for the exercise rehabilitation strategy of metabolic myopathies.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping