RESUMEN
Muscle contractures are a prominent and disabling feature of many neuromuscular disorders, including the 2 most common forms of childhood neurologic dysfunction: neonatal brachial plexus injury (NBPI) and cerebral palsy. There are currently no treatment strategies to directly alter the contracture pathology, as the pathogenesis of these contractures is unknown. We previously showed in a mouse model of NBPI that contractures result from impaired longitudinal muscle growth. Current presumed explanations for growth impairment in contractures focus on the dysregulation of muscle stem cells, which differentiate and fuse to existing myofibers during growth, as this process has classically been thought to control muscle growth during the neonatal period. Here, we demonstrate in a mouse model of NBPI that denervation does not prevent myonuclear accretion and that reduction in myonuclear number has no effect on functional muscle length or contracture development, providing definitive evidence that altered myonuclear accretion is not a driver of neuromuscular contractures. In contrast, we observed elevated levels of protein degradation in NBPI muscle, and we demonstrate that contractures can be pharmacologically prevented with the proteasome inhibitor bortezomib. These studies provide what we believe is the first strategy to prevent neuromuscular contractures by correcting the underlying deficit in longitudinal muscle growth.
Asunto(s)
Bortezomib/antagonistas & inhibidores , Contractura/metabolismo , Contractura/prevención & control , Músculo Esquelético/crecimiento & desarrollo , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo , Animales , Animales Recién Nacidos , Plexo Braquial/metabolismo , Contractura/genética , Modelos Animales de Enfermedad , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Enfermedades Neuromusculares/genética , Enfermedades Neuromusculares/prevención & control , Factor de Transcripción PAX7/genética , Factor de Transcripción PAX7/metabolismo , Complejo de la Endopetidasa Proteasomal/genética , Células Madre , TranscriptomaRESUMEN
Skeletal muscle adapts to external stimuli such as increased work. Muscle progenitors (MPs) control muscle repair due to severe damage, but the role of MP fusion and associated myonuclear accretion during exercise are unclear. While we previously demonstrated that MP fusion is required for growth using a supra-physiological model (Goh and Millay, 2017), questions remained about the need for myonuclear accrual during muscle adaptation in a physiological setting. Here, we developed an 8 week high-intensity interval training (HIIT) protocol and assessed the importance of MP fusion. In 8 month-old mice, HIIT led to progressive myonuclear accretion throughout the protocol, and functional muscle hypertrophy. Abrogation of MP fusion at the onset of HIIT resulted in exercise intolerance and fibrosis. In contrast, ablation of MP fusion 4 weeks into HIIT, preserved exercise tolerance but attenuated hypertrophy. We conclude that myonuclear accretion is required for different facets of exercise-induced adaptive responses, impacting both muscle repair and hypertrophic growth.