During Muscle Atrophy Induced by Denervation, as Occurs with Aging, the Ubiquitin Ligase Trim32 Catalyzes the Loss of Desmin Cytoskeleton and Attached Myofibrils

Background: Skeletal muscle atrophy is a debilitating response to loss of muscle innervation (i.e. denervation), as occurs during aging, spinal cord injuries and many human diseases including motor-neuron diseases, diabetes and cancer. The major fraction being degraded during atrophy is the myofibrils, the loss of which accounts for reduced strength, fatigue and disability. The mechanism for turnover of myofibrils during atrophy has long been uncertain, although the ubiquitin-proteasome system seems to play a major role.

Methods: In this study we used a sophisticated in vivo electroporation approach and advanced biochemical techniques to study the order of events leading to myofibril destruction during the slow atrophy induced by denervation.

Results: We show that myofibril destruction in denervated muscle is preceded and accelerated by the depolymerization of the desmin cytoskeleton. Desmin depolymerization requires phosphorylation and ubiquitination by the ubiquitin ligase Trim32. Downregulation of Trim32 in denervated muscles by the electroporation of a shRNA prevented desmin disassembly and attenuated the loss of myofibrils, especially of thin filament. The muscles expressing shRNA to Trim32 also exhibited a major preservation of mass. Interestingly, proteolytic fragments of desmin accumulated in muscles 10 days after denervation, and thus preceded the loss of actin and myosin from the myofibril. Furthermore, enhanced dissociation of desmin filaments by the expression of a dominant negative accelerated myofibril destruction seven days after denervation.

Conclusion: Thus, during atrophy, desmin depolymerization precedes and accelerates myofibril breakdown, and the complete loss of desmin is not required for myofibril destruction.