Related Experiment Video
Updated: Apr 28, 2026
Assessing Functional Performance in the Mdx Mouse Model
Published on: March 27, 2014
Caspase-12 ablation preserves muscle function in the mdx mouse
Catherine Moorwood1, Elisabeth R Barton2
1Department of Anatomy and Cell Biology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA and Pennsylvania Muscle Institute, University of Pennsylvania, Philadelphia, PA, USA.
Abstract:
Duchenne muscular dystrophy (DMD) is a devastating muscle wasting disease caused by mutations in dystrophin. Several downstream consequences of dystrophin deficiency are triggers of endoplasmic reticulum (ER) stress, including loss of calcium homeostasis, hypoxia and oxidative stress. During ER stress, misfolded proteins accumulate in the ER lumen and the unfolded protein response (UPR) is triggered, leading to adaptation or apoptosis. We hypothesized that ER stress is heightened in dystrophic muscles and contributes to the pathology of DMD. We observed increases in the ER stress markers BiP and cleaved caspase-4 in DMD patient biopsies, compared with controls, and an increase in multiple UPR pathways in muscles of the dystrophin-deficient mdx mouse. We then crossed mdx mice with mice null for caspase-12, the murine equivalent of human caspase-4, which are resistant to ER stress. We found that deleting caspase-12 preserved mdx muscle function, resulting in a 75% recovery of both specific force generation and resistance to eccentric contractions. The compensatory hypertrophy normally found in mdx muscles was normalized in the absence of caspase-12; this was found to be due to decreased fibre sizes, and not to a fibre type shift or a decrease in fibrosis. Fibre central nucleation was not significantly altered in the absence of caspase-12, but muscle fibre degeneration found in the mdx mouse was reduced almost to wild-type levels. In conclusion, we have identified heightened ER stress and abnormal UPR signalling as novel contributors to the dystrophic phenotype. Caspase-4 is therefore a potential therapeutic target for DMD.
Insights
Endoplasmic reticulum (ER) stress exacerbates Duchenne muscular dystrophy (DMD). Blocking ER stress marker caspase-4 in mice significantly improved muscle function and reduced degeneration, identifying it as a potential therapeutic target for DMD.
Area of Science:
- Biomedical Science
- Molecular Biology
- Genetics
Background:
- Duchenne muscular dystrophy (DMD) is a severe genetic disorder characterized by progressive muscle degeneration.
- Dystrophin deficiency in DMD leads to cellular stress, including endoplasmic reticulum (ER) stress, due to factors like calcium imbalance, hypoxia, and oxidative stress.
- ER stress activates the unfolded protein response (UPR), which can result in cell adaptation or programmed cell death (apoptosis).
Purpose of the Study:
- To investigate the role of ER stress and UPR signaling in the pathology of DMD.
- To determine if heightened ER stress contributes to the dystrophic phenotype in muscles.
- To evaluate the therapeutic potential of targeting ER stress pathways in DMD.
Main Methods:
- Analysis of ER stress markers (BiP and cleaved caspase-4) in DMD patient muscle biopsies.
- Assessment of UPR pathways in muscles of dystrophin-deficient mdx mice.
- Genetic deletion of caspase-12 (murine equivalent of human caspase-4) in mdx mice to assess resistance to ER stress and its impact on muscle pathology.
Main Results:
- DMD patient biopsies showed elevated levels of ER stress markers compared to controls.
- Muscles from mdx mice exhibited increased activity in multiple UPR pathways.
- Deletion of caspase-12 in mdx mice led to a 75% recovery in muscle force generation and eccentric contraction resistance.
- Caspase-12 deletion normalized compensatory hypertrophy by reducing fiber size and significantly decreased muscle fiber degeneration.
Conclusions:
- Heightened ER stress and aberrant UPR signaling are novel contributors to the dystrophic phenotype in DMD.
- Caspase-4 emerges as a significant factor in DMD pathology.
- Targeting caspase-4 presents a promising therapeutic strategy for Duchenne muscular dystrophy.
