Plum is a novel regulator of synaptic function and muscle size inD. melanogaster

ABSTRACT Alterations in the neuromuscular system underlie several neuromuscular diseases and play critical roles in the development of sarcopenia, the age-related loss of muscle mass and function. Mammalian Myostatin (MST) and GDF11, members of the TGF-β superfamily of growth factors, are powerful regulators of muscle size in both model organisms and humans. Myoglianin (MYO), the Drosophila homolog of MST and GDF11, is a strong inhibitor of synaptic function and structure at the neuromuscular junction (NMJ), and a negative regulator of body weight and muscle size and function in flies. Here, we identified Plum, a cell surface immunoglobulin homologous to mammalian developmental regulators Protogenin and Nope, as a modulator of MYO function in the larval neuromuscular system. Reduction of Plum specifically in the larval body-wall muscles abolishes the previously demonstrated positive effect of attenuated MYO signalling on both muscle size and neuromuscular junction structure and function, likely by de-sequestrating the remaining MYO. In addition, downregulation of Plum on its own results in decreased synaptic strength and body weight, classifying Plum as a (novel) regulator of neuromuscular function and body (muscle) size. These findings offer new insights into possible regulatory mechanisms behind ageing- and disease-related neuromuscular dysfunctions in humans and identify potential targets for therapeutic interventions.