Langerak Shaughna, Kim Myung-Jun, Lamberg Hannah, Godinez Michael, Main Mackenzie, Winslow Lindsey, O'Connor Michael B, Zhu Changqi C
Department of Biological Sciences, Ferris State University, Big Rapids, MI 49307, USA.
Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA.
Biol Open. 2018 Apr 26;7(4):bio029454. doi: 10.1242/bio.029454.
The 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 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.This article has an associated First Person interview with the first author of the paper.
激活素信号通路至少利用三种不同的配体——激活素-β（Actβ）、懒散蛋白（Daw）和肌生成抑制素（Myo）——来调节果蝇幼虫发育的几个一般方面，包括细胞增殖、神经元重塑和新陈代谢。在此，我们提供实验证据表明，Daw和Myo都是成年果蝇中的抗衰老因子。在成年果蝇中敲低Myo或Daw会缩短平均寿命，而在成年肌肉组织而非脂肪组织中过表达任何一种配体则会延长平均寿命。对成年肌肉中泛素化蛋白聚集体的检查显示，Myo或Daw启动的激活素信号与泛素化蛋白聚集体的数量之间存在强烈的负相关。我们表明，这种相关性具有重要的功能意义，通过证明在成年果蝇肌肉中敲低26S蛋白酶体调节亚基Rpn1可以完全消除成年肌肉组织中野生型Daw或Myo过表达所引起的寿命延长效应，并且成年肌肉中Daw或Myo过表达所导致的寿命延长可能是由于26S蛋白酶体关键亚基的蛋白质水平升高。总体而言，我们的数据表明，成年肌肉中由Myo和Daw启动的激活素信号部分地通过直接或间接调节26S蛋白酶体水平来调节蛋白质稳态，从而影响寿命。由于Myo与脊椎动物肌肉质量调节因子肌肉生长抑制素（GDF8）和肌肉生长抑制素旁系同源物GDF11密切相关，我们的观察结果可能为探究GDF11/8在脊椎动物衰老调节中的作用提供一个新的实验模型。本文有一篇与该论文第一作者的相关第一人称访谈。
