Small‐caliber skeletal muscle fibers do not suffer necrosis in mdx mouse dystrophy

Abstract

The prevalence of internal nuclei in muscle fibers (centronucleation), which is a reliable cumulative index of all prior muscle fiber necrosis, was measured at different ages in different muscles of mdx mice and was correlated with muscle fiber diameter. The prevalence of centronucleated fibers (as percentage of total number of fibers) rose gradually after age 20 days until it reached a peak level of 80% at age 60 days. No significant centronucleation (or necrosis) was observed in the following circumstances: in 4 different limb muscles before age 15 days, in leg muscles that were denervated by peripheral nerve section or rendered immobile by high thoracic cordotomy at 15 days, or in rotator extraocular muscles throughout the animals' life span. In these situations, muscle fiber diameter remained below approximately 20 micron. The mechanism by which small-diameter fibers are resistant to necrosis in mdx dystrophy is unknown, but a similar situation exists in hamster and Duchenne muscular dystrophy.

Adenovirus-mediated dystrophin minigene transfer improves muscle strength in adult dystrophic (MDX) mice

“…Here we show for the first time that even in muscles of immunologically mature mdx animals that have undergone previous cycles of myofiber necrosis, AdV-mediated dystrophin minigene transfer is able to significantly ameliorate histopathological changes, provided that adequate immunosuppressive treatment is also given to allow the maintenance of dystrophin expression. To the extent that the prevalence of central nuclei within the mdx soleus muscle at 8 weeks of age (ie the age of vector administration in the present study) has been shown to be approximately 55%, 13 our finding of a similar prevalence of central nucleation in mdx soleus muscles 2 months after AdV-Dys injection suggests that further episodes of myofiber necrosis may have been minimal to absent following vector delivery. Additionally, an interesting observation was that dystrophin gene transfer to the soleus appeared to exert a protective effect (as determined by the prevalence of central nucleation) not only on those fibers demonstrating detectable dystrophin expression, but also on neighboring fibers that were dystrophin-negative in the same muscle section.…”

“…Therefore, quantification of the prevalence of central nucleation within mdx myofibers provides a useful index of the antecedent level of muscle necrosis. [13][14][15] Since AdV-Dys was administered to adult mdx animals that had already undergone cycles of necrosis, central nucleation was present within a substantial proportion of fibers at the time of gene transfer. In this regard, Figure 4 demonstrates that both centrally and peripherally nucleated myofibers were effectively transduced at 5 days after AdV-Dys delivery to adult mdx muscle.…”

“…9,10 Muscle sections were also counterstained with hematoxylin and eosin (H & E) to allow determination of the prevalence of centrally nucleated myofibers, an indicator of the degree of previous necrosis and regeneration in mouse muscles. [13][14][15] Microscopically visualized sections were photographed using a video camera and the image was stored on a Macintosh computer. Analysis of the number and cross-sectional area of dystrophin-positive and dystrophin-negative myofibers on the entire muscle cross-section (averaging approximately 1500 and 700 myofibers for diaphragm and soleus, respectively) was performed using the public domain program NIH Image (version 1.49).…”

Acetylcholine Receptors in Innervated Muscles of DystrophicmdxMice Degrade as after Denervation

“…mdx mouse muscles begin a major cycle of degeneration and regeneration that stabilizes in most muscles by 10 weeks of age (Settles et al, 1996). The mice we used were between 10 and 12 weeks of age, which is when the majority of muscle fibers is resistant to additional degradation (Karpati et al, 1988). Furthermore, even after 12 d in organ culture, md x muscles were still healthy and fibrillating.…”

Methods and biomarkers for the diagnosis and prognosis of cancer and other diseases: Towards personalized medicine

“…In adult muscle, with the exception of a few intra-fusal (muscle spindle) fibers, muscle fibers display peripherally-located myonuclei. Central myofiber nuclei are apparent only in those parts of muscle fibers that have undergone one or more regenerative events, and CNI is used as an index of accumulated disease progression (Karpati et al, 1988). An early NMR spectroscopy study correlated a number of metabolites including peaks from taurine in a muscle sample, with CNI in sections of the same muscle (McIntosh et al, 1998a).…”