Zebrafish genetic model of neuromuscular degeneration associated with Atrogin-1 expression

作者：Romain Menard, Elena Morin, Dexter Morse, Caroline Halluin, Marko Pende, Aissette Baanannou, Janelle Grendler, Heath Fuqua, Jingjing Li, Ludovic Lancelot, Jessica Drent, Frédéric Bonnet, Joel H. Graber, Prayag Murawala, Cédric Dray, Jean‐Philippe Pradère, James A. Coffman, Romain Madelaine · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.03.07.642048 · 研究领域：Muscle Physiology and Disorders、Adipose Tissue and Metabolism、Prosthetics and Rehabilitation Robotics

model organisms of accelerated muscle degeneration and atrophy. The zebrafish undergoes aging, with hallmarks including mitochondrial dysfunction, telomere shortening, and accumulation of senescent cells. However, zebrafish age slowly, and no specific zebrafish models of accelerated muscle atrophy associated with molecular events of aging are currently available. We have developed a new genetic tool to efficiently accelerate muscle-fiber degeneration and muscle-tissue atrophy in zebrafish larvae and adults. We used a gain-of-function strategy with a molecule that has been shown to be necessary and sufficient to induce muscle atrophy and a sarcopenia phenotype in mammals: Atrogin-1 (also named Fbxo32). We report the generation, validation, and characterization of a zebrafish genetic model of accelerated neuromuscular atrophy, the atrofish. We demonstrated that Atrogin-1 expression specifically in skeletal muscle tissue induces a muscle atrophic phenotype associated with locomotion dysfunction in both larvae and adult fish. We identified degradation of the myosin light chain as an event occurring prior to muscle-fiber degeneration. Biological processes associated with muscle aging such as proteolysis, inflammation, stress response, extracellular matrix (ECM) remodeling, and apoptosis are upregulated in the atrofish. Surprisingly, we observed a strong correlation between muscle-fiber degeneration and reduced numbers of neuromuscular junctions in the peripheral nervous system, as...