Proteostasis Dysregulation in Postnatal Muscle Growth and Neuromuscular Contractures

Skeletal muscle growth involves two general processes: (1) addition of myonuclei to growing multinucleated myofibers (myonuclear accretion), and (2) protein synthesis within the myofibers. Although we have found neonatal denervation to cause dysregulation of satellite cells, the muscle stem cells that add nuclei to growing myofibers, we have discovered that complete neonatal denervation does not impair myonuclear accretion, and that neonatal inhibition of myonuclear accretion does not impair longitudinal muscle growth. These findings rule out a role for myonuclear accretion in longitudinal muscle growth and contractures, contrary to common assumptions. Instead, we have identified that protein degradation is elevated in denervated muscle, counteracting maintained protein synthesis. We have further identified that pharmacologic blockade of protein degradation prevents contractures in our model. This finding (1) confirms a role for protein degradation in contracture pathogenesis, (2) demonstrates as proof of concept that contractures can be prevented by pharmacologically targeting the underlying pathophysiology, and (3) demonstrates the utility of our model for both scientific discovery and preclinical testing of novel strategies. This breakthrough in the understanding of the pathogenesis and potential treatment of contractures is published in JCI Insight.*

However, in order to safely translate such a treatment strategy to humans, we must seek opportunities to more precisely target the specific mechanisms at play. With our current work, we are further delineating the specific signaling pathways responsible for the altered protein degradation within denervated muscle. We are also determining the mechanistic role of protein degradation in regulating longitudinal muscle growth, a process that is largely unexplored. This research is currently funded by the National Institutes of Health – Eunice Kennedy Shriver National Institute of Child Health and Human Development.

*Proteasome inhibition preserves longitudinal growth of denervated muscle and prevents neonatal neuromuscular contractures. Nikolaou S, Cramer AA, Hu L, Goh Q, Millay DP, Cornwall R. JCI Insight. 2019 Dec 5;4(23).