Severely Atrophic Human Muscle Fibers With Nuclear Misplacement Survive Many Years of Permanent Denervation

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Abstract

Likewise in rodents, after complete 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 severely atrophic muscle fibers. Up to two years of LMN denervation the muscle fibers with nuclear clumps are very seldom, but in this cohort of patients the severely atrophic muscle fibers are frequent in muscle biopsies harvested three to six years after SCI. Indeed, the percentage increased to 27 ± 9% (p< 0.001), and then abruptly decreased from the 6th year onward, when fibrosis takes over to neurogenic muscle atrophy. Immunohistochemical analyses shown that nuclear misplacements occurred in both fast and slow muscle fibers. In conclusion, human muscle fibers survive permanent denervation much longer than generally accepted and relocation of nuclei is a general behavior in long term denervated muscle fibers.

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RYR1 mutations are a common cause of congenital myopathies with central nuclei.

S Abbs, C. Sewry, S. Treves … (2010)

Centronuclear myopathy (CNM) is a rare congenital myopathy characterized by prominence of central nuclei on muscle biopsy. CNM has been associated with mutations in MTM1, DNM2, and BIN1 but many cases remain genetically unresolved. RYR1 encodes the principal sarcoplasmic reticulum calcium release channel and has been implicated in various congenital myopathies. We investigated whether RYR1 mutations cause CNM. We sequenced the entire RYR1 coding sequence in 24 patients with a diagnosis of CNM from South Africa (n = 14) and Europe (n = 10) and identified mutations in 17 patients. The most common genotypes featured compound heterozygosity for RYR1 missense mutations and mutations resulting in reduced protein expression, including intronic splice site and frameshift mutations. The high incidence in South African patients (n = 12/14) in conjunction with recurrent RYR1 mutations associated with common haplotypes suggested the presence of founder effects. In addition to central nuclei, prominent histopathological findings included (often multiple) internalized nuclei and type 1 fiber predominance and hypotrophy with relative type 2 hypertrophy. Although cores were not typically seen on oxidative stains, electron microscopy revealed subtle abnormalities in most cases. External ophthalmoplegia, proximal weakness, and bulbar involvement were prominent clinical findings. Our findings expand the range of RYR1-related phenotypes and suggest RYR1 mutations as a common cause of congenital myopathies with central nuclei. Corresponding to recent observations in X-linked CNM, these findings indicate disturbed assembly and/or malfunction of the excitation-contraction machinery as a key mechanism in CNM and related myopathies.

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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?

Ugo Carraro, Simona Boncompagni, M. Zanin … (2004)

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 microm, while the FES-trained subjects have more that 50% of myofibers larger than 30 microm. 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.

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Structural differentiation of skeletal muscle fibers in the absence of innervation in humans.

Simona Boncompagni, Katia Rossini, Christian Hofer … (2007)

The relative importance of muscle activity versus neurotrophic factors in the maintenance of muscle differentiation has been greatly debated. Muscle biopsies from spinal cord injury patients, who were trained with an innovative protocol of functional electrical stimulation (FES) for prolonged periods (2.4-9.3 years), offered the unique opportunity of studying the structural recovery of denervated fibers from severe atrophy under the sole influence of muscle activity. FES stimulation induced surprising recovery of muscle structure, mass, and force even in patients whose muscles had been denervated for prolonged periods before the beginning of FES training (up to 2 years) and had almost completely lost muscle-specific internal organization. Ninety percent (or more) of the fibers analyzed by electron microscopy showed a striking recovery of the ultrastructural organization of myofibrils and Ca(2+)-handling membrane systems. This functional/structural restoration follows a pattern that mimics some aspects of normal muscle differentiation. Most importantly, the recovery occurs in the complete absence of motor and sensory innervation and of nerve-derived trophic factors, that is, solely under the influence of muscle activity induced by electrical stimulation.

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Author and article information

Journal

Journal ID (nlm-ta): Eur J Transl Myol

Journal ID (iso-abbrev): Eur J Transl Myol

Journal ID (publisher-id): EJTM

Title: European Journal of Translational Myology

Publisher: PAGEPress Publications, Pavia, Italy

ISSN (Print): 2037-7452

ISSN (Electronic): 2037-7460

Publication date (Electronic): 13 June 2016

Publication date Collection: 13 June 2016

Volume: 26

Issue: 2

Electronic Location Identifier: 5894

Affiliations

[(1) ]IRCCS, Fondazione Ospedale San Camillo , Venice, Italy

[(2) ]Institute of Physical Medicine and Rehabilitation , Wilhelminenspital, Vienna, Austria

[(3) ]Ludwig Boltzmann Institute of Electrical Stimulation and Physical Rehabilitation , Vienna, Austria

Author notes

I.R.C.C.S. Fondazione Ospedale San Camillo. Via Alberoni, 70-30126 Venezia-Lido, Italy +39 338 1575745 ugo.carraro@ 123456ospedalesancamillo.net

Conflict of Interest

The author declare no conflict of interests.

Article

DOI: 10.4081/ejtm.2016.5894

PMC ID: 4942702

PubMed ID: 27478559

SO-VID: 19c8a042-0c07-407a-ad81-6e3a309f0887

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This article is distributed under the terms of the Creative Commons Attribution Noncommercial License ( by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

Severely Atrophic Human Muscle Fibers With Nuclear Misplacement Survive Many Years of Permanent Denervation

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Most cited references 14

RYR1 mutations are a common cause of congenital myopathies with central nuclei.

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?

Structural differentiation of skeletal muscle fibers in the absence of innervation in humans.

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