Abstract
BackgroundAbnormal branched myofibers within skeletal muscles are commonly found in diverse animal models of muscular dystrophy as well as in patients. Branched myofibers from dystrophic mice are more susceptible to break than unbranched myofibers suggesting that muscles containing a high percentage of these myofibers are more prone to injury. Previous studies showed ubiquitous over-expression of mouse olfactory receptor 23 (mOR23), a G protein-coupled receptor, in wild type mice decreased myofiber branching. Whether mOR23 over-expression specifically in skeletal muscle cells is sufficient to mitigate myofiber branching in dystrophic muscle is unknown.MethodsWe created a novel transgenic mouse over-expressing mOR23 specifically in muscle cells and then bred with dystrophic (mdx) mice. Myofiber branching was analyzed in these two transgenic mice and membrane integrity was assessed by Evans blue dye fluorescence.ResultsmOR23 over-expression in muscle led to a decrease of myofiber branching after muscle regeneration in non-dystrophic mouse muscles and reduced the severity of myofiber branching in mdx mouse muscles. Muscles from mdx mouse over-expressing mOR23 significantly exhibited less damage to eccentric contractions than control mdx muscles.ConclusionsThe decrease of myofiber branching in mdx mouse muscles over-expressing mOR23 reduced the amount of membrane damage induced by mechanical stress. These results suggest that modifying myofiber branching in dystrophic patients, while not preventing degeneration, could be beneficial for mitigating some of the effects of the disease process.Electronic supplementary materialThe online version of this article (doi:10.1186/s13395-016-0077-7) contains supplementary material, which is available to authorized users.
Highlights
Abnormal branched myofibers within skeletal muscles are commonly found in diverse animal models of muscular dystrophy as well as in patients
Results mouse olfactory receptor 23 (mOR23) transgenic mice To determine the role of mOR23 in regulating myofiber branching in muscle cells, we created a novel transgenic mouse over-expressing mOR23 under the control of the human skeletal actin (HSA) promoter, a muscle-specific promoter (Fig. 1a)
Branched myofibers tends to break at the branch point thereby decreasing the ability of myofibers to properly contract [5, 21]. Another key finding in our studies was that a decrease of myofiber branching in dystrophic muscle via the over-expression of mOR23 in muscle cells improved membrane integrity in response to mechanical stress induced by a stretch of eccentric contractions. These results suggest that modifying myofiber branching in dystrophic patients, while not preventing degeneration, could be beneficial for mitigating some of the effects of the disease process
Summary
Abnormal branched myofibers within skeletal muscles are commonly found in diverse animal models of muscular dystrophy as well as in patients. Branched myofibers from dystrophic mice are more susceptible to break than unbranched myofibers suggesting that muscles containing a high percentage of these myofibers are more prone to injury. Whether mOR23 over-expression in skeletal muscle cells is sufficient to mitigate myofiber branching in dystrophic muscle is unknown. Duchenne muscular dystrophy (DMD) is an X-linked disease due to the absence of dystrophin in muscle [1] that affects about one in every 3500 boys [2]. Myofiber branching negatively impacts dystrophic muscles as demonstrated using extensor digitorum longus (EDL) muscles from dystrophin-deficient mdx mice. Unbranched and branched myofibers isolated from mdx EDL muscles were subjected to Ca2+-force activation. Branched myofibers broke before reaching maximal calcium activation, whereas unbranched myofibers were able to sustain
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