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Updated: Apr 28, 2026
Immunolabelling Myofiber Degeneration in Muscle Biopsies
Published on: December 5, 2019
P38α MAPK underlies muscular dystrophy and myofiber death through a Bax-dependent mechanism
Erin R Wissing1, Justin G Boyer1, Jennifer Q Kwong1
1Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, 240 Albert Sabin Way, Cincinnati, OH 45229, USA.
Abstract:
Muscular dystrophies are a group of genetic diseases that lead to muscle wasting and, in most cases, premature death. Cytokines and inflammatory factors are released during the disease process where they promote deleterious signaling events that directly participate in myofiber death. Here, we show that p38α, a kinase in the greater mitogen-activated protein kinase (MAPK)-signaling network, serves as a nodal regulator of disease signaling in dystrophic muscle. Deletion of Mapk14 (p38α-encoding gene) in the skeletal muscle of mdx- (lacking dystrophin) or sgcd- (δ-sarcoglycan-encoding gene) null mice resulted in a significant reduction in pathology up to 6 months of age. We also generated MAPK kinase 6 (MKK6) muscle-specific transgenic mice to model heightened p38α disease signaling that occurs in dystrophic muscle, which resulted in severe myofiber necrosis and many hallmarks of muscular dystrophy. Mechanistically, we show that p38α directly induces myofiber death through a mitochondrial-dependent pathway involving direct phosphorylation and activation of the pro-death Bcl-2 family member Bax. Indeed, muscle-specific deletion of Bax, but not the apoptosis regulatory gene Tp53 (encoding p53), significantly reduced dystrophic pathology in the muscles of MKK6 transgenic mice. Moreover, use of a p38 MAPK pharmacologic inhibitor reduced dystrophic disease in Sgcd(-/-) mice suggesting a future therapeutic approach to delay disease.
Insights
p38α kinase is a key regulator in muscular dystrophy, driving muscle cell death. Inhibiting p38α or its downstream target Bax significantly reduces disease pathology in mouse models, suggesting a potential therapeutic strategy.
Area of Science:
- Cell Biology
- Genetics
- Biochemistry
Background:
- Muscular dystrophies are genetic disorders causing progressive muscle wasting and premature death.
- Inflammatory cytokines contribute to myofiber death in muscular dystrophy.
- The mitogen-activated protein kinase (MAPK) signaling pathway plays a role in cellular stress responses.
Purpose of the Study:
- To investigate the role of p38α kinase in the pathogenesis of muscular dystrophy.
- To explore p38α as a potential therapeutic target for muscular dystrophy.
Main Methods:
- Genetic deletion of Mapk14 (p38α) in mouse models of muscular dystrophy (mdx and sgcd null).
- Generation of muscle-specific transgenic mice overexpressing MKK6 to model heightened p38α signaling.
- Assessment of dystrophic pathology, myofiber necrosis, and apoptosis.
- Investigating the role of Bax and p53 in p38α-mediated muscle cell death.
- Pharmacological inhibition of p38 MAPK in Sgcd(-/-) mice.
Main Results:
- Deletion of Mapk14 in dystrophic mice significantly reduced pathology.
- MKK6 transgenic mice exhibited severe myofiber necrosis and muscular dystrophy hallmarks.
- p38α directly induces myofiber death via a mitochondrial pathway involving Bax activation.
- Muscle-specific deletion of Bax, but not p53, reduced pathology in MKK6 transgenic mice.
- Pharmacological inhibition of p38 MAPK ameliorated disease in Sgcd(-/-) mice.
Conclusions:
- p38α kinase is a critical regulator of signaling pathways leading to muscle cell death in muscular dystrophy.
- Targeting p38α or its downstream effector Bax represents a promising therapeutic strategy for muscular dystrophy.
- Pharmacological inhibition of p38 MAPK may offer a viable approach to delay disease progression.
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