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Expression of trypsin-like proteases and protease nexin-1 in mdx mouse muscles
Hitoshi Sawada1, Yuhsuke Kikukawa, Susumu Ban
1Sugashima Marine Biological Laboratory, Graduate School of Science, Nagoya University, 517-0004 Toba, Japan. hsawada@bio.nagoya-u.ac.jp
Abstract:
In order to examine the possible participation of trypsin-like proteases in the onset and progress of muscular dystrophy, we investigated the expression of the trypsin-like protease in muscular tissues in mdx mice. We found that the mRNAs of several trypsin-like proteases, including hepsin and t-PA, were expressed in the muscular tissues of mdx mice, but at levels not significantly different from normal mice. Since the enzymatic properties of dystrypsin, a muscle trypsin-like protease activated before onset of the disease, are similar to those of thrombin, we investigated the expression pattern of thrombin in mdx mouse muscles. The results showed that prothrombin mRNA is up-regulated in mdx mice at 20-30 days of age but not before the age of 15 days (preclinical). Since protease nexin-1 (PN-1) is known to be a physiological inhibitor of thrombin, we also examined the expression pattern of PN-1. We found that PN-1 transcription and translation is down-regulated in the muscular tissues of mdx mice, before the onset of clinical symptoms. These results suggest that thrombin may be involved in the progression of muscular dystrophy or the regeneration of muscle fibers after the onset of the disease and that the reduced level of PN-1 may enhance the activities stimulate the activities of muscle proteases, including dystrypsin, at a preclinical stage in mdx mice.
Insights
Reduced protease nexin-1 (PN-1) levels in mdx mice suggest thrombin involvement in muscular dystrophy progression. This preclinical downregulation may enhance muscle protease activity before disease onset.
Area of Science:
- Biochemistry
- Molecular Biology
- Muscle Physiology
Background:
- Muscular dystrophy involves complex molecular pathways.
- Trypsin-like proteases are implicated in various physiological and pathological processes.
- Understanding protease roles in muscular dystrophy pathogenesis is crucial for therapeutic development.
Purpose of the Study:
- To investigate the role of trypsin-like proteases in muscular dystrophy using the mdx mouse model.
- To examine the expression patterns of thrombin and its inhibitor, protease nexin-1 (PN-1), in mdx mouse muscles.
Main Methods:
- Analysis of trypsin-like protease mRNA expression (hepsin, t-PA) in mdx mouse muscle tissue.
- Quantitative analysis of prothrombin mRNA expression in mdx mice at different age points.
- Assessment of protease nexin-1 (PN-1) transcription and translation in mdx mouse muscle.
Main Results:
- Hepsin and t-PA mRNA levels were not significantly different between mdx and normal mice.
- Prothrombin mRNA was upregulated in mdx mice between 20-30 days of age, a preclinical stage.
- Protease nexin-1 (PN-1) transcription and translation were downregulated in mdx mice before clinical symptoms appeared.
Conclusions:
- Thrombin may play a role in muscular dystrophy progression or muscle regeneration post-onset.
- Downregulation of PN-1 in preclinical stages may potentiate the activity of muscle proteases like dystrypsin.
- These findings suggest a potential therapeutic window targeting protease activity in muscular dystrophy.
