How selective is the reinnervation of skeletal muscle fibers?

A multitude of mechanisms during development seem to be responsible for the matching of a given motoneuron “type” and its intended target. There can be specificity of the target at the level of a given muscle, the region of the muscle (in both its crosssectional and rostrocaudal axes), and the fiber phenotype within that region. These mechanisms appear to be operational during embryonic, fetal, and neonatal development, resulting in near-perfect matching, at least with respect to the level of a general muscle fiber phenotype in the normal adult. In this issue of the Journal, Wang et al. report that after completely resecting a 12-mm segment of the tibial nerve above the knee and then suturing the nerve segment at the same site (but with the axial orientation rotated by 180°) in adult rats, a motoneuron of a given type has a high probability of projecting back to the region of a muscle that it normally innervates. That is, the regions of several hindlimb muscles that normally have a high proportion of slow fibers persisted after 21 months of reinnervation. These results suggest the presence of guidance cues that increase the probability of “slow” and “fast” motoneurons being directed toward the region of the muscle having more slow or fast muscle fiber phenotypes, respectively. The authors also found that the average interfiber distance of slow fibers was shorter in reinnervated than in control muscles, suggesting that there was some conversion of phenotypes from a fast to slow phenotype following reinnervation. Many experiments have been designed to identify those guidance cues that are present during development. Similarly, experiments have been conducted to identify whether there are neural– muscular matching cues for a given muscle, muscle region, or muscle fiber phenotype in the adult following peripheral nerve injury. Both motoneuron– muscle fiber phenotype matching and muscle fiber conversion of phenotypes to match motoneuron properties have been demonstrated in a wide range of experimental paradigms and species. The results from some of these papers have been interpreted as demonstrating the presence of one mechanism rather than another. There is more than adequate evidence, however, demonstrating the presence of multiple guidance cues that result in a “preferred” matching of a motoneuron with a given muscle fiber phenotype after injury. It also is clear that during neuromuscular reinnervation in the adult, some ability exists to convert some muscle fibers to an appropriate phenotype. Fiber type conversion, however, is not obligatory. For example, when a mixed muscle is reinnervated following denervation, it appears that a given type of motoneuron will make the appropriate match in the majority of instances. However, when motoneuron–muscle fiber phenotype mismatches occur among muscle fibers within a single motor unit, they are not always corrected by converting the muscle fiber phenotype. This can result in a combination of phenotypes among the fibers of an individual motor unit. In some motor units, however, there is either perfect matching as a result of some combination of guidance cues or conversion of the fibers to a given phenotype when mismatches occur. Thus, previously published data, as well as the paper by Wang et al., suggest that phenotype conversion is not the sole mechanism in establishing muscle unit homogeneity following reinnervation of muscles in the adult. In the adult, the accessibility and efficacy of a given set of cues that direct a motor axon to its target seem to affect the accuracy and even success of a motoneuron reaching that target. For example, disrupting the normal spatial relationships between the spinal cord and the roots from which the motoneurons normally project seems to eliminate the strength of some cues. The distance from the target at which the peripheral nerve is injured or disrupted Correspondence to: V.R. Edgerton; e-mail: vre@ucla.edu