Abstract:

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease characterized by neuromuscular junction (NMJ) disruption, motor neuron (MN) axon degeneration, and neuronal death. Unfortunately, there is currently no effective treatment available for ALS and consequently, most patients die several years post diagnosis. The neurodegeneration that occurs in ALS is considered to be a non-cell autonomous process involving interactions between the motor neuron and its diverse extracellular microenvironments via an unknown mechanism. Distal Axonopathy is one of the early disease signs; however, the involvement and contribution of neighboring tissues and specifically, the muscle environment to the disease pathology remain controversial. Few works have concluded that muscles play a minor role or none at all in ALS pathology. For example, reducing hSOD ^G93A directly in the muscles of the SOD ^G93A mouse model, as well as crossing lipoxygenase (LOX) SOD ^G37R  with the Cre coding sequence under the control of the muscle creatine kinase (MCK) promoter, or performing manipulations using follistatin did not affect the disease’s onset and survival. Moreover, application of muscle condition media (CM) from SOD ^G93A -expressing muscles on healthy spinal cord neurons or embryonic stem cell-derived motor neurons in vitro resulted in no appreciable effect. In contrast with these findings, overexpressing SOD^G93A protein specifically in healthy skeletal muscle results in severe muscle atrophy and induces an ALS phenotype. In addition, expressing hSOD1 with G37A and G93A gene variants only in skeletal muscles led to limb weakness, NMJ abnormalities, MN axon degeneration, and cell death, suggesting a direct role for muscles in ALS physiology. Recently, we have characterized a mechanism by which the diseased muscles contribute to the motor neuron degeneration observed in ALS. Using a simplified micro-fluidic chamber (MFC) for studying muscle and motor neuron interactions, we demonstrated that ALS-mutant muscles affect MN axons. Our results show that ALS-mutant muscles facilitate a delay in axon growth towards the muscle compartment, axon degeneration, and NMJ disruption. However, eventually the connections between axons and muscles are established. Thus, at least in our system, apparently the non-cell autonomous contributions of the muscle are insufficient to recapitulate all the toxic effects observed in ALS. Interestingly, once the MNs also carries an ALS mutation, the axons are more susceptible to degeneration by mutated muscle CM. Therefore, apparently although the muscles have contribution to ALS progression, MNs are key in ALS physiology.