Atrophy, oxidative switching and ultrastructural defects in skeletal muscle of Ataxia Telangiectasia mouse model.

Ataxia Telangiectasia is a rare, multi system disease caused by ATM kinase deficiency. Atm knockout mice recapitulate premature aging, immunodeficiency, cancer predisposition, growth retardation and motor defects but not cerebellar neurodegeneration and ataxia. We explored if Atm loss is responsible of skeletal muscle defects by investigating myofiber morphology, oxidative/glycolytic activity, myocyte ultrastructural architecture and neuromuscular junctions. Atm knockout mice showed reduced muscle and fiber size. Atrophy, protein synthesis impairment and switch from glycolytic to oxidative fibers were detected along with an increase of slow and fast myosin expression levels in tibialis anterior and solei muscles isolated from Atm knockout mice. Transmission electron microscopy of tibialis anterior revealed misalignments of z-lines and sarcomeres and mitochondria abnormalities, that were associated with increase of reactive oxygen species. Moreover, neuromuscular junctions appeared larger and more complex compared to Atm wild-type mice, but with preserved presynaptic terminals.In conclusion, we report for the first time that Atm knockout mice have clear morphological skeletal muscle defects that will be relevant to investigate oxidative stress response, motor alteration and the interplay with peripheral nervous system in Ataxia Telangiectasia.