The Drosophila TGF-beta/Activin-like ligands Dawdle and Myoglianin appear to modulate adult lifespan through regulation of 26S proteasome function in adult muscle

Abstract

The Drosophila Activin signaling pathway employs at least three separate ligands – Activin-β (Actβ), Dawdle (Daw), and Myoglianin (Myo) – to regulate several general aspects of fruit fly larval development, including cell proliferation, neuronal remodeling, and metabolism. Here we provide experimental evidence indicating that both Daw and Myo are anti-ageing factors in adult fruit flies. Knockdown of Myo or Daw in adult fruit flies reduced mean lifespan, while overexpression of either ligand in adult muscle tissues but not in adipose tissues enhanced mean lifespan. An examination of ubiquitinated protein aggregates in adult muscles revealed a strong inverse correlation between Myo- or Daw-initiated Activin signaling and the amount of ubiquitinated protein aggregates. We show that this correlation has important functional implications by demonstrating that the lifespan extension effect caused by overexpression of wild-type Daw or Myo in adult muscle tissues can be completely abrogated by knockdown of a 26S proteasome regulatory subunit Rpn1 in adult fly muscle, and that the prolonged lifespan caused by overexpression of Daw or Myo in adult muscle could be due to enhanced protein levels of the key subunits of 26S proteasome. Overall, our data suggest that Activin signaling initiated by Myo and Daw in adult Drosophila muscles influences lifespan, in part, by modulation of protein homeostasis through either direct or indirect regulation of the 26S proteasome levels. Since Myo is closely related to the vertebrate muscle mass regulator Myostatin (GDF8) and the Myostatin paralog GDF11, our observations may offer a new experimental model for probing the roles of GDF11/8 in ageing regulation in vertebrates.

Modulators of hormonal response regulate temporal fate specification in the Drosophila brain

“…Fly stocks used were as follows: UAS-Kr-h1-HA [FlyORF#F000495], GAL80-asense [18], UAS-dSmad2-CA [36] and babo 9 [10]. The following stocks were obtained from the Bloomington Stock Center (BSC): hs-FLP , tubP-GAL80 , FRT19A ; UAS-mCD8 :: GFP (BL#5134), tubP-GAL80 , FRTG13 (BL#5140), tubP-GAL80 , FRT40A (BL#5192), hs-FLP , UAS-mCD8 :: GFP (BL#28832), UAS-mCD8 :: GFP (BL#5130), GAL4-c708 (BL#50743), GAL4-Repo (BL#7415), UAS-Myoglianin RNAi (BL#31200) [37, 38, 39], UAS-EcR-B1 ΔC655 . W650A (BL#6872), tub-GAL80 TS (BL#7017), UAS-EcR-B1 (BL#6469), UAS-EcR-A (BL#6470), LexA-GMR26E01 (α’β’-driver; BL#54617), LexAop-mCD8-GFP (BL#32203; BL#32205), UAS-mCD8-GFP (BL#32194), GAL4-OK107 (BL#854), UAS-Luciferase RNAi (BL#31603), UAS-Kr-h1 RNAi (BL#50685), UAS-LacZ (BL#1777), GAL4-worniu (BL#56553), GAL4- c305a (BL#30829), d Smad2 1 (BL#44384), babo 32 (BL#5399), babo k16912 (BL#11207), chinmo 1 (BL#59969), UAS-babo-CA (BL#64293) and Kr-h1 10642 (BL#12380).…”

Hobbit regulates intracellular trafficking to drive insulin-dependent growth duringDrosophiladevelopment

“…S5D). Other tissues, including the midgut (Song et al, 2017), prothoracic gland (Colombani et al, 2005) and muscles (Demontis et al, 2014;Langerak et al, 2018) also secrete signals that influence systemic growth and regulation; however, RNAi knockdown of hobbit in these tissues had no significant effect on body size (Fig. S4D), suggesting that hobbit is primarily required in the IPCs and fat body to regulate systemic growth.…”

Divergence of Drosophila species: Longevity and reproduction under different nutrient balances

“…One of the critical tissues that require TGF-β/activin signaling for larval adaptation is muscle (Watanabe et al, 2019). In addition to these studies on the larval responses in gene expression and metabolism, how Daw-initiated TGF-β/activin signaling regulates functions of adult tissues and influences life span has been investigated on standard laboratory foods (Bai, Kang, Hernandez, & Tatar, 2013;Chang et al, 2019;Langerak et al, 2018); and intriguingly, adult muscles also depend on TGF-β/activin signaling to control the 26S proteasome level and realize normal life span (Langerak et al, 2018). Confusingly, however, two studies report opposing effects of whole-body knockdown of daw on life span (Bai et al, 2013;Langerak et al, 2018).…”

“…In addition to these studies on the larval responses in gene expression and metabolism, how Daw-initiated TGF-β/activin signaling regulates functions of adult tissues and influences life span has been investigated on standard laboratory foods (Bai, Kang, Hernandez, & Tatar, 2013;Chang et al, 2019;Langerak et al, 2018); and intriguingly, adult muscles also depend on TGF-β/activin signaling to control the 26S proteasome level and realize normal life span (Langerak et al, 2018). Confusingly, however, two studies report opposing effects of whole-body knockdown of daw on life span (Bai et al, 2013;Langerak et al, 2018). It requires future research to address whether the specialists, when they are aging on the M diet, show responses reminiscent of what have been found in their larvae and in the D. melanogaster daw mutant and whether such responses exert detrimental effects on longevity.…”