Severely Atrophic Muscle Fibers with Nuclear Clumps Survive many Years in Permanently Denervated Human Muscle

Abstract

After complete lumbar-ischiatic spinal cord injury (SCI) the lower motor neuron (LMN) denervated human muscle fibers lose completely the myofibrillar apparatus and the coil distribution of myonuclei that are relocated in groups (nuclear clumps) in the center of these "severely atrophic" muscle fibers. In our cohort of patients, the "severely atrophic" myofibers are frequent in muscle biopsies harvested three to six years after SCI. Up to two years of LMN denervation the muscle fibers with nuclear clumps are 2 ± 5% (mean ± SD) of the total muscle fibers. The percentage increases to 27 ± 9% between three and six years of denervation (p< 0.001), and then abruptly decrease from the 6th year of LMN denervation onward, when fibrosis takes over to neurogenic muscle atrophy. Immunohistochemical analyses show that nuclear grouping occurs in both fast and slow muscle fibers. These results show that human muscle fibers survive permanent denervation much longer than generally accepted.

3D false color computed tomography for diagnosis and follow-up of permanent denervated human muscles submitted to home-based Functional Electrical Stimulation

“…36 Finally, muscles enter severe atrophy, wherein myofibers undergo the internalization of subsarcolemmal myonuclei, resulting in the regrouping of tens of myonuclei within the center of myofibers and the complete disappearance of long segments of the contractile apparatus. 13 Eventually, muscle fibers all but completely disappear, while fibrous and adipose tissue accumulates.…”

“…37 Additional investigations in human patients showed that irrecoverable muscle tissue degeneration can be delayed up to three years, and indeed light microscopy analysis showed that myofibers retain at least 30% of their initial size over this duration, confirming at least a two-year window for possible FES intervention. [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] However, electron microscopy investigations on patients biopsies indicated that the decay of excitationcontraction contractile apparatus, i.e., of t-tubules and triads, starts within one year of denervation, suggesting that for the best results the h-b FES treatment must start as early as possible. 14,15,17 …”

“…66 Complete LMN denervated muscles are, indeed, soon unable to sustain tension during tetanic contractions induced by electrical stimulation, as the long-lasting severe atrophy of the permanently inactive muscles is worsened by the replacement of myofibers with adipocytes and collagen. [13][14][15][16][17][18][67][68][69] As previously mentioned, there is a clear rationale for the existence of a window of opportunity to initiate muscle stimulation that may not only delay or avoid muscle degeneration in LMN-denervated patients, but could also recover contractility of the atrophic muscles. While several stimulators and rehabilitation strategies are commercially available for performing FES on patients with upper motor neuron damage due to SCI, for patients suffering from complete LMN damage, the protocols and home-based system developed and tested by the EU program "RISE" (Vienna, Austria) is the clear gold standard.…”

“…Here, we review the results of one such case study, involving the use of a customized false-color 3D computed tomography (CT) protocol for the imaging of the rectus femoris of spinal cord injury (SCI) patients suffering from complete and permanent denervation, as characterized by complete Conus and Cauda Equina syndrome. [12][13][14][15][16][17][18] Home-based functional electrical stimulation (h-bFES) was applied in these persons using customized electrical stimulators with large electrodes that covered nearly the entirety of the thigh ventral surface. [14][15][16][17][18][19][20][21][22][23][24][25][26] The use the reported falsecolor 3D CT imaging protocol highlights its utility in both confirming the diagnosis of long-term denervation and in quantifying the progression of muscle atrophy to degeneration.…”

2012 Autumn Padua Muscle Days | Padova and Terme Euganee, Italy, November 23-25

“…The bioenergetic function of mitochondria in a tissue is evaluated by OXPHOS analysis and depends on mitochondrial structure and function [1][2][3][4]. Mitochondrial structure or mt-density is determined by measurement of mtmarkers normalized for tissue mass or volume.…”