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Updated: May 28, 2026
Studying Muscle Transcriptional Dynamics at Single-molecule Scales in Drosophila
Published on: September 8, 2023
A muscle-specific p38 MAPK/Mef2/MnSOD pathway regulates stress, motor function, and life span in Drosophila
Alysia Vrailas-Mortimer1, Tania del Rivero, Subhas Mukherjee
1Cell Biology Department, Emory University School of Medicine, Whitehead Building, Room No. 435, Atlanta, GA 30322, USA.
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.
Insights
A novel p38 MAP kinase (p38K) pathway involving Mef2 and MnSOD regulates stress and lifespan in Drosophila. This pathway, primarily in muscles, impacts aging and mitochondrial function.
Area of Science:
- Molecular biology
- Aging research
- Genetics
Background:
- The molecular underpinnings of aging and stress response are complex and not fully elucidated.
- Identifying coregulators of stress resilience and lifespan is crucial for understanding aging.
Purpose of the Study:
- To investigate the role of a p38 MAP kinase (p38K)/Mef2/MnSOD pathway in regulating stress and lifespan in Drosophila.
- To elucidate the mechanistic link between p38K, Mef2, and MnSOD in aging and stress response.
Main Methods:
- Utilized Drosophila melanogaster as a model organism.
- Employed genetic manipulation including overexpression and inhibition of p38K.
- Performed muscle-restricted and neuronal add-back experiments.
- Assessed phenotypes such as lifespan, motor function, stress sensitivity, protein carbonylation, and metabolic response to hypoxia.
Main Results:
- Overexpression of p38K extended lifespan in a MnSOD-dependent manner.
- p38K inhibition led to early lethality, motor deficits, and increased stress sensitivity.
- These deficits were rescued by muscle-specific but not neuron-specific p38K restoration.
- p38K mutations correlated with increased protein carbonylation and altered Nrf2-dependent transcription and hypoxia response.
- p38K was shown to regulate mitochondrial MnSOD expression via the Mef2 transcription factor.
Conclusions:
- A muscle-restricted p38K-Mef2-MnSOD signaling module acts as a coregulator of lifespan and stress response in Drosophila.
- This pathway is distinct from the insulin/JNK/FOXO pathway.
- Enhancing p38K activity may restore mitochondrial detoxification and combat age-related stress.
