Two parallel neuronal circuits involving electrical synapse and DAF-7/TGF-β signaling regulate muscle autophagy in C....

The systemic coordination of autophagy during development remains poorly understood. Here, we identify two parallel neuronal circuits that regulate the autophagy-lysosome pathway in the body wall muscle of C. elegans. One circuit, utilizing UNC-7/UNC-9 electrical synapses between AVA interneurons and A-type motor neurons (A-MNs), promotes autophagy by inhibiting neuropeptide release from A-MNs. The other employs the TGF-β-like molecule DAF-7, secreted from ASI sensory neurons, which activates autophagy via the canonical TGF-β pathway. These pathways converge to regulate cytosolic Ca²⁺ levels in the muscle, thereby maintaining lysosomal integrity. Disruption of either circuit elevates Ca²⁺, overactivating calpain. This leads to the accumulation of non-degradative autolysosomes and accelerates muscle degeneration. Our findings elucidate a neuronal mechanism for controlling muscle autophagy and provide insights into the pathogenesis of neurogenic myopathy.