Induced Myogenesis in Long-Term Permanent Denervation: Perspective Role in Functional Electrical Stimulation of Denervated Legs in Humans

Long-term permanent denervation (LT-PD) induces severe atrophy of skeletal muscle accompanied by apoptotic loss of myonuclei. Morphologic characteristics of the long-term denervated muscle suggest that the original fibers are lost and those seen are the results of repeated cycles of cell death and regeneration. Myoblasts and myotubes express peculiar myosins. Light and heavy chains of embryonic myosin are sensitive indicators of myogenic events in adult muscles. Electrical stimulation of permanent denervated muscle increases the mean size of the myofibers, maintains the sarcomeres and possibly prevents secondary degeneration and apoptosis/necrosis. Mechanisms underlying the recruitment of satellite cells for regenerative or hypertrophic processes have not been established, but cytokine interactions among macrophages and satellite cells seem to be essential. Here we show that long-term denervated muscles increase in size and change their myosin content after full regeneration is induced by bupivacaine treatment. After transient expression of embryonic myosin, fast myosins prevail in all the experimental muscles. In spite of a severe atrophy (around 90%), ten days after injury the regenerated muscles have twice the area at the muscle belly of the respective long-term denervated muscles. Since satellite cells activity is required for extreme hypertrophy of overloaded adult muscles or eutrophy after severe atrophy in recovering muscles, positive regulation of activation, division and fusion of myoblasts could be an important tool to understand limits of recovery of neurogenic muscle myopathies by functional electrical stimulation (FES). Pilot studies in humans show that standing up with denervated muscles using functional electrical stimulation is a reality in permanent complete denervation.