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

Abstract

Summary Molecular mechanisms that concordantly regulate stress, lifespan and age-related physiological changes remain incompletely understood. Here, we demonstrate that in Drosophila, a p38 MAP Kinase (p38K)/Mef2/MnSOD pathway is a co-regulator of stress and lifespan in vivo. Hence, over-expression of p38K extends lifespan in a MnSOD-dependent manner, while 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 lifespan 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.

MKP-1 coordinates ordered macrophage-phenotype transitions essential for stem cell-dependent tissue repair

“…Generating and characterizing mouse models with cell type-specific inactivation of MKP-1 should provide powerful biological tools to address the role of this phosphatase in the regulation of inflammation and stem cell responses during tissue repair in physiological and pathological conditions. For instance, dysregulated p38 activity has been associated with the aging process, 64,65 which, considering the prominent role of inflammation in the control of regeneration, might be linked to the decline of muscle regenerative capacity during aging. 3 Furthermore, we propose that the pro-to anti-inflammatory polarization switch of macrophages during the process of tissue repair after injury shares a similar function to that occurring during endotoxin tolerance.…”

In Vivo Interaction Proteomics Reveal a Novel p38 Mitogen-Activated Protein Kinase/Rack1 Pathway Regulating Proteostasis in Drosophila Muscle

“…2F). Consistent with this model, transgenic overexpression of Sod2 in muscle tissue rescues the effect of p38b deficiency on longevity (17). Therefore, we sought to explore the link between the enhanced protein aggregation we observed in p38b mutant muscle and ROS induction.…”

“…Control of the oxidative damage caused by ROS in the adult fly muscle has emerged as a key mechanism linking p38b activity to life-span (17). In the proposed pathway, p38b potentiates the Mef2-driven expression of the mitochondrial superoxide dismutase (Sod2), thereby limiting the effects of ROS (Fig.…”

“…Flies were raised on a standard cornmeal-agar-molasses medium at 25°C. p38b⌬45 and upstream activation sequence (UAS)-p38bKD flies were previously described (17). UAS-Sod2 and GMR-Gal4 flies were kindly donated by A. Hilliker and H. McNeill, respectively.…”

“…Although the role of p38 in mammalian myogenesis is well established (reviewed in references 15 and 16), less is known about its function in aging muscle. A recent study demonstrated that p38b, one of two p38 MAPKs in Drosophila, modulates reactive oxygen species (ROS)-mediated damage in thoracic muscle (17). At least two pathways appear to be involved: Mef2-driven expression of MnSOD (Sod2) and Nrf2-dependent suppression of Keap1.…”