Proteostasis Dysregulation in Postnatal Muscle Growth and Neuromuscular Contractures
Skeletal muscle growth involves two general processes:
- Addition of myonuclei to growing multinucleated myofibers (myonuclear accretion), and
- Protein synthesis within the myofibers.
We have found that complete neonatal denervation does not impair myonuclear accretion, and that neonatal inhibition of myonuclear accretion does not impair longitudinal muscle growth. 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 mouse model of NBPI. This breakthrough in the understanding of the pathogenesis and potential treatment of contractures is published in JCI Insight1 (Figure 2).
In order to safely translate such a treatment strategy to humans, we must seek opportunities to more precisely target the specific mechanisms at play. We are currently working to delineate the specific signaling pathways responsible for the altered protein degradation within denervated muscle. We have identified that myostatin signaling, a potent negative regulator of muscle size, mediates protein degradation and contractures in a sex-specific manner. Furthermore, pharmacologic blockade of myostatin signaling partially prevents contractures and restores muscle growth in our mouse model of NBPI. These key mechanistic insights in contracture pathogenesis are published in eLife.2
With our current work, we continue to investigate mechanisms of contracture pathogenesis by exploring intracellular pathways downstream of myostatin, such as ERK signaling and JNK signaling, in order to identify novel targets for contracture therapy.3 This research is currently funded by the National Institutes of Health – Eunice Kennedy Shriver National Institute of Child Health and Human Development.
1. 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).
2. Sex-specific role of myostatin signaling in neonatal muscle growth, denervation atrophy, and neuromuscular contractures. Emmert ME, Aggarwal P, Shay-Winkler K, Lee SJ, Goh Q, Cornwall R. eLife. 2022 Oct 31;11.
3. Elucidating the JNK Signaling Pathway in Neonatal Muscle Growth and Neuromuscular Contractures. Shao K and Shoates M, Barrios D, Conte S, Tarabishi A, Velaga G, Shay-Winkler K, Goh Q, Cornwall R. bioRxiv. 2026 July 1.
