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Contractile properties of diaphragm muscle segments from old mdx and old transgenic mdx mice
G S Lynch1, J A Rafael, R T Hinkle
1Institute of Gerontology, University of Michigan, Ann Arbor 48109-2007, USA.
Abstract:
Diaphragm muscles of young (4- to 6-mo-old) mdx mice show severe fiber necrosis and have normalized forces and powers 60 and 46% of the values for control C57BL/10 mice. In contrast, microinjection of mdx mouse embryos with a truncated dystrophin minigene has produced young transgenic mdx (tg-mdx) mice with a level of dystrophin expression and structural and functional properties of diaphragm muscle strips measured in vitro not different from those of control mice. Whether dystrophin expression and functional corrections persist for the life span of these animals is not know. We tested the null hypothesis that, in old (24 mo) tg-mdx mice, dystrophin expression is adequate and diaphragm muscle strips have forces and powers not different from values for diaphragm muscle strips from young tg-mdx mice or control mice. Compared with control values, diaphragm muscle strips from old mdx mice had normalized forces and powers of 48 and 31%, respectively. Expression of dystrophin persisted in diaphragm muscles of old tg-mdx mice, and functional properties were not different from diaphragm muscles of young tg-mdx or young or old control mice. These results suggest that, with a transgenic animal approach, dystrophin expression and functional corrections persist for the life span of the animals.
Insights
Transgenic mdx mice with a dystrophin minigene showed restored diaphragm function. This functional correction persisted throughout their lifespan, indicating a potential long-term therapeutic approach for muscular dystrophy.
Area of Science:
- Biomedical Science
- Genetics
- Muscle Physiology
Background:
- Mdx mice, a model for Duchenne muscular dystrophy, exhibit severe diaphragm muscle fiber necrosis.
- Young mdx mice show significantly reduced muscle forces and powers compared to controls.
- Transgenic approaches aim to restore dystrophin expression and function.
Purpose of the Study:
- To determine if dystrophin expression and functional improvements in diaphragm muscles persist throughout the lifespan of transgenic mdx (tg-mdx) mice.
- To test the hypothesis that old tg-mdx mice maintain adequate dystrophin levels and diaphragm muscle function.
Main Methods:
- Comparison of diaphragm muscle strips from young and old mdx mice, tg-mdx mice, and control C57BL/10 mice.
- Assessment of dystrophin expression levels.
- In vitro measurement of muscle forces and powers.
Main Results:
- Old mdx mice exhibited normalized forces and powers of 48% and 31% of control values, respectively.
- Dystrophin expression persisted in the diaphragm muscles of old tg-mdx mice.
- Functional properties of diaphragm muscle strips from old tg-mdx mice were comparable to those of young tg-mdx and control mice (young and old).
Conclusions:
- Transgenic expression of a dystrophin minigene leads to persistent functional correction of diaphragm muscles throughout the lifespan of mdx mice.
- This study supports the potential of gene replacement therapy for long-term management of muscular dystrophy.
- The findings suggest that the transgenic animal model is a viable platform for studying long-term therapeutic effects.