# Deciphering the pathophysiology of childhood neuromuscular contractures

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $389,550

## Abstract

ABSTRACT
 Cerebral palsy (CP) and neonatal brachial plexus injury (NBPI) are the two most common causes of
paralysis in children. Both conditions cause secondary contractures, or loss of joint flexibility, that are the
primary driver of physical disability and need for surgical treatment. These contractures cannot be cured by
existing therapies because the cause of these contractures is unknown. Through development of a mouse
model of NBPI we discovered that contractures are caused by impaired longitudinal muscle growth, resulting
from loss of normal nerve input during a critical neonatal window of muscle development. Understanding the
mechanisms by which denervation impairs neonatal muscle growth is critical to preventing these contractures.
We have made important discoveries regarding neuronal control and mechanisms of muscle growth and
contractures. First, we have discovered that longitudinal muscle growth does not require efferent innervation,
but rather afferent and/or sympathetic innervation. Second, we have discovered that longitudinal growth is
modulated by protein degradation rather than by protein synthesis or myonuclear accretion. Importantly, we
have found that pharmacologic inhibition of protein degradation prevents contractures in our NBPI 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. With our current proposed work, we will further delineate the relative roles of afferent and
sympathetic innervation through surgical and pharmacological manipulation of these specific innervation types.
This strategy will narrow our search for the mechanisms by which innervation regulates muscle growth and
development. We will also delineate the specific signaling pathways responsible for the altered protein
degradation within denervated muscle, using genetic and pharmacologic manipulation of relevant protein
synthesis and degradation pathways. We will therefore be able to tailor therapeutic strategies by recapitulating
the appropriate neuronal input and/or correcting the specific protein balance perturbation. In so doing, we will
also contribute to the scientific knowledge of the roles of innervation and basic growth processes in postnatal
muscle growth and development, with critical relevance to many childhood-onset neuromuscular and
musculoskeletal disorders.

## Key facts

- **NIH application ID:** 10116437
- **Project number:** 5R01HD098280-03
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Roger Cornwall
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $389,550
- **Award type:** 5
- **Project period:** 2019-05-06 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10116437

## Citation

> US National Institutes of Health, RePORTER application 10116437, Deciphering the pathophysiology of childhood neuromuscular contractures (5R01HD098280-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10116437. Licensed CC0.

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