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

Abstract

The Myostatin/Activin branch of the TGF superfamily acts as a negative regulator of mammalian skeletal muscle size, in part, through downregulation of insulin/IGF-1 signaling.Surprisingly, recent studies in Drosophila indicate that Activin signaling acts as a positive regulator of muscle size. In this study, we demonstrate that Drosophila Activin signaling positively regulates the InR/dTORC1 pathway and the level of MHC, an essential sarcomeric protein, via promoting the transcription of Pdk1 and Akt1. Enhancing InR/dTORC1 signaling in the muscle of Activin pathway mutants restores MHC levels close to wild-type, but only increased the width of muscle cells. In contrast, hyperactivation of the Activin pathway increases the length of muscle cells even when MHC levels were lowered by suppression of dTORC1.Together, these results indicate that Drosophila Activin pathway regulates larval muscle geometry via promoting InR/dTORC1-dependent MHC production and the differential assembly of sarcomeric components into either pre-existing (width) or new (length) sarcomeric units depending on the balance of InR/dTORC1 and Activin signals.

Muscle-derived Myoglianin regulates Drosophila imaginal disc growth

“…Intriguingly however, we find that loss of Actβ , another ligand that signals through Babo and dSmad2, results in a smaller muscles ( Moss-Taylor et al, 2019 ) contrary to that produced by loss of vertebrate Mstn and various other vertebrate Activin family members. Recent data has shown that DrosophilaActβ is the only Activin-like ligand that affects muscle growth, and it does so, in part, by regulating Insulin/Tor signaling in the opposite direction compared to vertebrates ( Kim and O’Connor, 2020 ). Thus, in Drosophila the Myo/Activin pathway promotes muscle growth while in vertebrates it inhibits muscle growth.…”

“…TGFβ mutants: myo 1 , Actβ 80 , daw 11 , dSmad2 F4 are described previously ( Awasaki et al, 2011 ; Peterson and O'Connor, 2013 ; Serpe and O'Connor, 2006 ; Zhu et al, 2008 ). The new myo CR2 allele is described in Kim and O’Connor, 2020 . Isoform miRNA lines for babo and myo-GAL4 are described previously ( Awasaki et al, 2011 ).…”

Insulin-Like Peptides and Cross-Talk With Other Factors in the Regulation of Insect Metabolism

“…Proper growth of muscles is dependent on ILP signalling. Research by Demontis and Perrimon (2009) and Kim and O’Connor (2021) showed that different components of ILP signalling may be important for the morphological properties (width, thickness, length) and ploidy of insect muscles. The results of these studies showed that the lack of ILP-dependent inhibition of the transcription factor FOXO led to a decrease in the size of D. melanogaster muscles ( Demontis and Perrimon, 2009 ).…”

“…Similar to its vertebrate homologues, Myc is a central regulator of the growth and proliferation of many cell types, including myocytes ( Gallant, 2013 ). Additionally, research carried out by Kim and O’Connor (2021) showed the importance of ILP signalling in the regulation of muscle growth in insects. The authors confirmed that Activin signalling promotes the growth of D. melanogaster muscles by positive regulation of the insulin receptor IR/TORC1 pathway and the level of Myosin heavy chain (Mhc) by increasing pdk1 and akt1 expression, genes encoding phosphoinositide-dependent kinase 1 and Akt kinase ( Gallant, 2013 ).…”

The Role of Muscle in Insect Energy Homeostasis

“…Insulin signaling in larval muscles is regulated by other signaling pathways including the TFG-β/Activin signaling pathway ligand Activin-β. Activin-β positively regulates insulin signaling and is required for proper muscle geometry and sarcomere protein level (Kim and O'Connor, 2020). While these studies show the importance of insulin signaling in proper muscle size and structure, whether insulin signaling in the muscle alters levels of stored glycogen locally or globally is unknown.…”