A Muscle-Specific p38 MAPK/Mef2/MnSOD Pathway Regulates Stress, Motor Function, and Life Span in Drosophila

Dev Cell. 2011 Oct 18;21(4):783-95. doi: 10.1016/j.devcel.2011.09.002.

Abstract

Molecular mechanisms that concordantly regulate stress, life span, and aging remain incompletely understood. Here, we demonstrate that in Drosophila, a p38 MAP kinase (p38K)/Mef2/MnSOD pathway is a coregulator of stress and life span. Hence, overexpression of p38K extends life span in a MnSOD-dependent manner, whereas inhibition of p38K causes early lethality and precipitates age-related motor dysfunction and stress sensitivity, that is rescued through muscle-restricted (but not neuronal) add-back of p38K. Additionally, mutations in p38K are associated with increased protein carbonylation and Nrf2-dependent transcription, while adversely affecting metabolic response to hypoxia. Mechanistically, p38K modulates expression of the mitochondrial MnSOD enzyme through the transcription factor Mef2, and predictably, perturbations in MnSOD modify p38K-dependent phenotypes. Thus, our results uncover a muscle-restricted p38K-Mef2-MnSOD signaling module that influences life span and stress, distinct from the insulin/JNK/FOXO pathway. We propose that potentiating p38K might be instrumental in restoring the mitochondrial detoxification machinery and combating stress-induced aging.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Blotting, Western
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / growth & development
  • Drosophila melanogaster / metabolism
  • Electrophoretic Mobility Shift Assay
  • Female
  • Hydrogen Peroxide / pharmacology
  • Immunoenzyme Techniques
  • JNK Mitogen-Activated Protein Kinases
  • Longevity*
  • Male
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Motor Neurons / pathology*
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Mutation / genetics
  • Myogenic Regulatory Factors / genetics*
  • Myogenic Regulatory Factors / metabolism
  • Oxidants / pharmacology
  • Oxidative Stress*
  • Protein Carbonylation
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase / metabolism
  • p38 Mitogen-Activated Protein Kinases / genetics*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Drosophila Proteins
  • Mef2 protein, Drosophila
  • Myogenic Regulatory Factors
  • Oxidants
  • RNA, Messenger
  • Hydrogen Peroxide
  • Superoxide Dismutase
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases