Myostatin-like proteins regulate synaptic function and neuronal morphology

Abstract

Growth factors of the TGFβ superfamily play key roles in regulating neuronal and muscle function. Myostatin (or GDF8) and GDF11 are potent negative regulators of skeletal muscle mass. However, expression of myostatin and its cognate receptors in other tissues, including brain and peripheral nerves, suggests a potential wider biological role. Here, we show that Myoglianin (MYO), the Drosophila homolog of myostatin and GDF11, regulates not only body weight and muscle size, but also inhibits neuromuscular synapse strength and composition in a Smad2-dependent manner. Both myostatin and GDF11 affected synapse formation in isolated rat cortical neuron cultures, suggesting an effect on synaptogenesis beyond neuromuscular junctions. We also show that MYO acts in vivo to inhibit synaptic transmission between neurons in the escape response neural circuit of adult flies. Thus, these anti-myogenic proteins act as important inhibitors of synapse function and neuronal growth.

DrosophilaActivin signaling promotes muscle growth through InR/dTORC1 dependent and independent processes

“…It is surprising that we find no effect of myo loss on muscle size since it is a clear homolog of vertebrate Mstn. Furthermore, it has been reported that RNAi knockdown of myo in muscles does result in a size increase, (Augustin, et al, 2017). These results are consistent with a negative role for Myo similar to Mstn its vertebrate counterpart.…”

Muscle-derived Myoglianin regulatesDrosophilaimaginal disc growth

“…Analysis of the null mutant in the present study indicates that it has little effect on muscle size. However a recent study employing a muscle-specific RNAi knockdown of myoglianin (myo), reported finding larger muscles similar to the vertebrate observation (Augustin et al, 2017). This discrepancy between the tissue-specific RNAi knockdown and the null phenotypes is something that is found relatively frequently in both Drosophila and also in vertebrates and may represent activation of compensatory pathways in the null phenotype that are not triggered by tissue specific knockdown (Di Cara and King-Jones, 2016; El-Brolosy and Stainier, 2017; El-Brolosy et al, 2019; Gibbens et al, 2011).…”

“…Myo is homologous to vertebrate Mstn, which negatively regulates skeletal muscle size by inhibiting proliferation of muscle stem cells (Morikawa et al, 2016) and regulation of protein homeostasis Rodriguez et al, 2014;Trendelenburg et al, 2009). Recent studies in Drosophila using RNAi tissue specific knockdown suggested that Myo also functions as a negative regulator of muscle size similarly to vertebrate Mstn (Augustin et al, 2017). We re-examined this issue using myo null alleles.…”

TGF-beta/Activin ligand Myoglianin couples muscle growth to the initiation of metamorphosis

“…The role of myo in holometabolous insects is not well known except for its functions in 126 muscles (Augustin et al, 2017;Lo and Frasch, 1999). Myo shares a 46% amino acid sequence 127 identity with the vertebrate Bone Morphogenetic Protein 11 (BMP11 or Growth differentiation 128 factor 11 (GDF11)) and Myostatin (or GDF8) (Lo and Frasch, 1999).…”

“…In Drosophila, Myo is expressed in 131 embryonic muscles as well as glial cells (Lo and Frasch, 1999). During the larval stage, Myo acts 132 like Myostatin at the neuromuscular junction (NMJ) to suppress synaptic transmissions and NMJ 133 growth and branching (Augustin et al, 2017). In addition, knockdown of muscle-derived myo 134 leads to increased muscle size and overall body size, indicating that Myo inhibits muscle growth 135 (Augustin et al, 2017).…”