Figure 1. The progression of cellular events that occurs in dystrophic mdx limb muscles.

(A) Time line showing the proportion of muscle fibers undergoing necrosis and regenerative events from birth to adulthood. There is little if any necrosis in the limb muscles of mdx mice prior to 3 wk of age [29], [73] when an abrupt onset of myofiber necrosis occurs [74]–[76]. By 4 wk of age approximately 30%–80% of the mdx muscles are characterized by inflammation, phagocytosis of necrotic tissue and early myogenesis; the rest of the myofibers remain essentially ‘intact’ [21], [73]. From 4 to 5 wk of age, myotubes form and damaged myofibers undergo regeneration [77]. In control mice myofibers are undamaged and grow by elongation and hypertrophy. After this initial bout of necrosis and as normal growth decelerates, the necrosis abates to a persistent low level (∼6%) from 8 to 12 wk of age [21], [26], [75]. However, even if only 3% of adult mdx myofibers undergo necrosis every day, ∼20% of the muscle tissue will be subjected to necrosis over one week. As the cycles of necrosis and subsequent active regeneration take about 3 wk, it can be calculated that ∼60% of adult mdx myofibers at any time are actively affected by necrosis and regeneration. (B) The time course of regenerative events after a single bout of myofiber necrosis. Within 1 d of damage, myofiber necrosis is evident histologically as fragmented sarcoplasm and the presence of inflammatory cells. Coincidently there is activation of myoblast proliferation followed by their differentiation and fusion into myotubes 3 to 7 d later [74], [78], [79]. The myotubes fuse with more myoblasts and each other over the next few days and after about 7 d, they fuse with the ends of the damaged myofibers [80]; coincidently, inflammatory cells decrease. Subsequently, myotubes and newly repaired segments of damaged myofibers hypertrophy and mature and may take a further 14 d [81]. Subsequently, the repaired fibers hypertrophy and undergo maturation attaining a stable adult size after approximately 3 weeks. Regenerated myofibers are identified by the presence of central myonuclei that persist for many months.