Persistent muscle fiber regeneration in long term denervation. Past, present, future

Abstract

Despite the ravages of long term denervation there is structural and ultrastructural evidence for survival of muscle fibers in mammals, with some fibers surviving at least ten months in rodents and 3-6 years in humans. Further, in rodents there is evidence that muscle fibers may regenerate even after repeated damage in the absence of the nerve, and that this potential is maintained for several months after denervation. While in animal models permanently denervated muscle sooner or later loses the ability to contract, the muscles may maintain their size and ability to function if electrically stimulated soon after denervation. Whether in mammals, humans included, this is a result of persistent de novo formation of muscle fibers is an open issue we would like to explore in this review. During the past decade, we have studied muscle biopsies from the quadriceps muscle of Spinal Cord Injury (SCI) patients suffering with Conus and Cauda Equina syndrome, a condition that fully and irreversibly disconnects skeletal muscle fibers from their damaged innervating motor neurons. We have demonstrated that human denervated muscle fibers survive years of denervation and can be rescued from severe atrophy by home-based Functional Electrical Stimulation (h-bFES). Using immunohistochemistry with both non-stimulated and the h-bFES stimulated human muscle biopsies, we have observed the persistent presence of muscle fibers which are positive to labeling by an antibody which specifically recognizes the embryonic myosin heavy chain (MHCemb). Relative to the total number of fibers present, only a small percentage of these MHCemb positive fibers are detected, suggesting that they are regenerating muscle fibers and not pre-existing myofibers re-expressing embryonic isoforms. Although embryonic isoforms of acetylcholine receptors are known to be re-expressed and to spread from the end-plate to the sarcolemma of muscle fibers in early phases of muscle denervation, we suggest that the MHCemb positive muscle fibers we observe result from the activation, proliferation and fusion of satellite cells, the myogenic precursors present under the basal lamina of the muscle fibers. Using morphological features and molecular biomarkers, we show that severely atrophic muscle fibers, with a peculiar cluster reorganization of myonuclei, are present in rodent muscle Muscle fiber regeneration in long term denervation

Displaced Myonuclei in Cancer Cachexia Suggest Altered Innervation

“…In addition to muscle-specific damage, another pathological condition leading to myonuclear misplacement and severe myofiber atrophy is denervation due to spinal cord injury or motor neuron toxicity. Myofibers survive denervation, but they show a typical nuclear misplacement consisting in nuclear clumps followed by stretches of anucleated (and amyofibrillar) sarcoplasm [30,47,48]. Denervation is also characterized by the specific upregulation of several molecular markers, including AchRs and Musk (which are involved in the NMJ) and NCAM and HDAC [46,49].…”

Myofiber Permeability and Force Production of Rat Muscles Following Eccentric Contractions: The Repeated Bout Effect Depends on the Interval

“…The numbers of d-MHC+/dystrophin+ myofibers were significantly elevated in the Pre 2nd bout_1w and Post 2nd bout_1w groups. It has been reported that regenerated myofibers are present in denervated muscles [29,30] and that denervation reversibly affects the domains of the membrane systems involved in excitation-contraction coupling [44]. Fast-velocity ECC (180˚/s) induces functional and structural damage to nerves [45].…”

“…In addition, calcium uptake during contractions is higher in fast-twitch myofibers than in slow-twitch myofibers [25], and fast-twitch fibers are more susceptible to ECC-induced muscle injury than slow-twitch fibers [26]. Myofiber regeneration can be evaluated using developmental myosin heavy chain (d-MHC) as an indicator, and d-MHC reactivity has been used to assess myofibers after ECC-induced muscle injury [27,28], and in denervated muscles [29,30].…”

Reactivation of Denervated Schwann Cells by Embryonic Spinal Cord Neurons to Promote Axon Regeneration and Remyelination

“…However, the main purpose of these studies was neuronal replacement, and it remains difficult to use the abovementioned cells to replace autologous neurons in clinical practice. Because the distal nerve stump may be less tolerating than muscle, a more practical strategy to improve regeneration is to maintain the distal nerve in an “available” state to accept the proximal axons [17]. A previous study used mesenchymal stem cell transplantation to activate denervated SCs in predegenerated nerves, but because the denervation time of the distal stump is short, the true utility of this approach is uncertain [31].…”

“…Sulaiman and Gordon confirmed that this time window was 6 months in rats [15]. In contrast, recent research believed that even if a rat has been denervated for more than 1 year, the muscle still has the ability to regenerate, which corresponds to better tolerance than nerves [16, 17]. Therefore, this study is aimed at determining the effect of transplanted embryonic neurons on SCs in distal nerve stumps in a rat peripheral nerve injury (PNI) model.…”