Long-Term Denervation in Humans Causes Degeneration of Both Contractile and Excitation-Contraction Coupling Apparatus, Which Is Reversible by Functional Electrical Stimulation (FES): A Role for Myofiber Regeneration?

Over the last 30 years there has been considerable interest in the use of functional electrical stimulation (FES) to restore movement to the limbs of paralyzed patients. Spinal cord injury causes a rapid loss in both muscle mass and contractile force. The atrophy is especially severe when the injury involves lower motoneurons because many months after spinal cord injury, atrophy is complicated by fibrosis and fat substitution. In this study we describe the effects of long-term lower motoneuron denervation of human muscle and present the structural results of muscle trained using FES. By means of an antibody for embryonic myosin, we demonstrate that many regenerative events continue to spontaneously occur in human long-term denervated and degenerated muscle (DDM). In addition, using electron microscopy, we describe i) the overall structure of fibers and myofibrils in long-term denervated and degenerated muscle, including the effects of FES, and ii) the structure and localization of calcium release units, or triads; the structures reputed to activate muscle contraction during excitation-contraction coupling (ECC). Both apparatus undergo disarrangement and re-organization following long-term denervation and FES, respectively. The poor excitability of human long-term DDM fibers, which extends to the first periods of FES training, may be explained in terms of the spatial disorder of the ECC apparatus. Its disorganization and re-organization following long-term denervation and FES, respectively, may play a key role in the parallel disarrangement and re-organization of the myofibrils that characterize denervation and FES training. The present structural studies demonstrate that the protocol used during FES training is effective in reverting long-term denervation atrophy and dystrophy. The mean fiber diameter in FES biopsies is 42.2 ± 14.8 SD (p < 0.0001 vs DDM 14.9 ± 6.0 SD); the mean percentile of myofiber area of the biopsy is 94.3 ± 5.7 SD (p < 0.0001 vs DDM 25.7 ± 23.7 SD); the mean percentile fat area is 2.1 ± 2.4 SD (p < 0.001 vs DDM 12.8 ± 12.1 SD); and the mean percentile connective tissue area is 3.6 ± 4.6 SD (p < 0.001 vs DDM 61.6 ± 20.1 SD). In DDM biopsies more than 50% of myofibers have diameter smaller than 10 μm, while the FES-trained subjects have more that 50% of myofibers larger than 30 μm. The recovery of muscle mass seems to be the result of both a size increase of the surviving fibers and the regeneration of new myofibers.