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.
Muscle contractures that limit joint motion are the primary driver of disability in many childhood neuromuscular disorders, yet there are no curative treatments since their cause is unknown. The goal of this project is to determine the roles of specific neural inputs and muscle protein balance mechanisms in longitudinal muscle growth and contracture formation in order to elucidate and correct the causative pathophysiologic mechanisms in neuromuscular contractures.
