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

• DOI: 10.1016/j.devcel.2011.09.002
• Publication Date: 2011-10-18T07:10:45Z
• Authors: Alysia Vrailas-Mo...; Tania del Rivero; Subhas Mukherjee; Sanjay Nag; Alexandros Gaitan...; Dimitris Kadas; Christos Consoulas; Atanu Duttaroy; Subhabrata Sanyal
• Keywords: Male; Motor Neurons; 0303 health sciences; Blotting, Western; Longevity; JNK Mitogen-Activated Protein Kinases; Electrophoretic Mobility Shift Assay; Hydrogen Peroxide; Oxidants; Mitochondria; Animals, Genetically Modified; Immunoenzyme Techniques; Protein Carbonylation; Oxidative Stress; 03 medical and health sciences; Drosophila melanogaster; Myogenic Regulatory Factors; Mutation; Animals; Drosophila Proteins; Female; Muscle, Skeletal; Developmental Biology

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.