Differential atrophy and fiber type-specific reactivation of myogenesis in denervated skeletal muscle

The interrelations of progressive muscle fiber atrophy and temporal and spatial patterns of compensatory neomyogenesis in denervated skeletal muscle are still poorly understood. Using indirect immunostaining for slow and fast isoforms of myosin, we found that in rat tibialis anterior muscle during the first two months after denervation the rate of atrophy of slow (type I) muscle fibers is significantly lower than that observed in fast (type II) muscle fibers. Cross-sectional areas (CSA) of fast fibers decreased by 4 %, 47%, 76% and 91% from the control levels by 10 days, 1, 2 and 4 months after denervation, respectively. Unlike fast fibers, CSA of slow fibers changed very little during the first two months after denervation, but dramatically decreased between months 2 and 4 after denervation. A subclass of slow fibers of small diameter comprising up to 12-16% of their population appeared in die tissue 2 months after denervation. Most of these small slow fibers were topographicaly associated with fast type fibers. Immunostaining for embryonic isomyosin has shown that activation of myogenesis occurred between months 1 and 2 after nerve transection, although at 10 days after denervation nascent myotubes were observed with a very low incidence. Experiments on co-localization of slow, fast and embryonic isoforms of myosin demonstrated that reactivation of myogenesis started and occurred predominantly on fast muscle fibers. At early stages of formation, developing myotubes were located under the basal laminae of the maternal fibers, and later they formed new basal laminae. Intrafusal fibers were more resistant to atrophy than extrafusal fibers, and some of them revealed enhanced reactivity for embryonic myosin. We found no correlation between the degree of atrophy of individual fibers and the capacity of their satellite cells to activate myogenesis. This indicates that a "critical point" in the loss of the mass of the fiber is not necessary for the myogenic response. Our data show that die myogenic response of satellite cells in denervated skeletal muscle is activated on live muscle fibers and, unlike reparative regenerative process, does not require the attainment of terminal stages of their degeneration and death.