Parallel Development of Bone and Muscle Impairments Following Neonatal Brachial Plexus Injury

ABSTRACT Neonatal brachial plexus injury (NBPI) is a traumatic perinatal neuromuscular injury causing muscle paralysis and lifelong arm impairment. Muscle paralysis in these children also leads to bone and joint consequences, including deformed growth of the scapula and humerus. These musculoskeletal impairments, and their negative impact on function, persist even if the nerve recovers. Perinatal paralysis occurs during a critical period of rapid musculoskeletal development, but almost nothing is understood about the parallel postnatal development of muscle and bone that drives these persistent deformities and resultant impaired function. Our primary hypothesis is that nerve injury directly affects bone formation and metabolism, and that restricted muscle growth induces additional deformity through mechanical and cell-signaling pathways. We will apply our unique rodent model of NBPI in an innovative experimental design that isolates effects of neural, muscle loading, and disuse effects on bone development to 1) determine direct effects of nerve injury on humeral and scapular postnatal development by employing a previously validated rat model of brachial plexus injury to assess metabolic, vascular, and microstructural changes in bone; and 2) determine the influence of impaired muscle development following NBPI on the parallel development of bone with nerve injury by evaluating muscle fibrosis, structure, and expression of factors important for muscle-bone crosstalk. This exploratory R21 project, conducted by a multidisciplinary team with expertise in orthopedic surgery and biomechanical engineering, has high potential to elucidate the role of denervation in the parallel development of bone and muscle that occurs postnatally. Unlike previous studies, in this project, we will be able to measure both effects of mechanical and metabolic factors on deformity formation. Our innovative study design permits us to isolate both direct neural effects on bone and indirect effects from altered muscle on bone development in a way that has not previously been possible. Ultimately, this work challenges the paradigm of an isolated focus on muscle as a treatment target to reduce or eliminate deformity by distinguishing interactions between bone and muscle during development after a nerve injury that underlie deformity and loss of function. We anticipate our results will provide new candidates for effective treatment of NBPI and other neuromuscular injuries.