| Popis: |
The motor unit (MU), comprised of a single lower motor neuron and all the muscle fibers it innervates, is the final common pathway of the neuromuscular system. Functional MUs are essential in executing the motor demands of the upper motor neurons. Several neuropathological stresses—including: amyotrophic lateral sclerosis (ALS), peripheral nerve injury (PNI), spinal muscular atrophy or aging—can converge at the MU, negatively affecting MU integrity. While various methods exist that can assess the different properties of the MU—connectivity and contractility—the relationship between these properties during neuropathological stress is still poorly understood.Here, we longitudinally measured MU integrity in models of ALS and PNI using a combination of MU connectivity, contractility and behavioral assessments. We found that loss of muscle contractility is an early defect of SOD1(G93A) mice—one model for ALS—and precedes MU connectivity decline, suggesting that muscle may also be an important early ALS therapeutic target site. We utilized longitudinal assessments of MU connectivity and behavior in SOD1(G93A) mice to determine the therapeutic efficacy of overexpressing small heat shock protein B1 (HSPB1), demonstrated to be neuroprotective in several neurodegenerative models, via AAV9-HSPB1 delivery. Our results indicated no significant neuroprotective effect in SOD1(G93A) mice receiving AAV9-HSPB1.We also longitudinally mapped MU regeneration following a PNI and demonstrated early contractility recovery that aligned with behavioral recovery, and preceding MU connectivity recovery. These results suggest a latent recovery phase of MU reconnectivity that follows early muscle strength recovery. Following a PNI, mice were treated with either AAV9-HSPB1 or AAV9-SMN to overexpress HSPB1 or survival motor neuron protein (SMN)—another potential neuroprotective protein. Our data did not demonstrate significant accelerated MU recovery following AAV9-HSPB1 or AAV9-SMN delivery. This body of work illustrates the strengths of longitudinally measuring MU connectivity and contractility. We propose novel pathological mechanisms underlying neuropathological insult to the MU which can potentially be targets for future therapeutics. Furthermore, we were able to more thoroughly assess the efficacy of potential therapeutics towards neuromuscular integrity. |
