A two stage model of skeletal muscle necrosis in muscular dystrophy : the role of fiber branching in the terminal stage

Branched fibers are a well-documented phenomenon of regenerating dystrophic skeletal muscle. They are found in the muscles of boys with Duchenne muscular dystrophy (DMD) and in the muscles of mdx “aged” mice, an animal model of DMD. However, only a handful of studies have investigated how the contractile properties of these morphologically deformed fibers differ from those of normal fibers in aged muscle. These studies have found an association between the extent of fiber branching and susceptibility to damage from eccentric contractions. They have also found that branched muscle fibers cannot sustain maximal contractions and that branch points are sites of increased mechanical stress. New imaging techniques like second harmonic imaging have revealed that the sub-cellular myofibrillar structure is greatly disturbed at branch points. These findings have important implications for understanding the function of dystrophin. It is commonly thought that dystrophin’s role is to mechanically stabilise the sarcolemma, as numerous studies have shown that eccentric contractions damage dystrophic muscle more than normal muscle. However, the finding that branched fibers are mechanically weakened raises the question: Is it the lack of dystrophin, or is it the fiber branching, that leads to the vulnerability of dystrophic muscle to contractile damage? The other question is how the presence of these branched fibers alters the contractile properties of “aged” dystrophic muscle. Throughout this chapter I will use the term branched to describe the malformed fibers. Most earlier studies use the terminology “split fiber”, but because it conjures up images of a Y-shaped bifurcation, with one adult fiber giving rise to two daughter fibers it is somewhat misleading as we now know many fibers, if not most display a complex syncytia of interconnecting branches. Some branches do not originate from the main fiber but are results of incomplete regeneration with myotubes fusing to repair the damaged adult fiber. Branching, I feel, is a more accurate description of the malformed fiber morphology. With respect to the branching terminology I am following the lead of Ontell & Feng, 1981 where they state “the term branched has been preferred because it describes an existing condition while the term split implies a mode formation. Unfortunately there is no immediate apparent substitute the terms parent and daughter”. Readers can make up their own mind on the split verse branched question by examining morphology of fibers in the following chapter.