Skeletal Muscles Do Not Undergo Apoptosis During Either Atrophy or Programmed Cell Death-Revisiting the Myonuclear Domain Hypothesis

Schwartz, Lawrence M.

doi:10.3389/fphys.2018.01887

Cited by 58 publications

(57 citation statements)

References 77 publications

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“…1e,f). While the mechanisms controlling apoptosis in a post-mitotic tissue such as skeletal muscle are not well understood and remain controversial 85 , this type of cell death has been observed in myofibers during other muscle wasting conditions 86 , in Lmna E82K mutant 87 and heterozygous Lmna +/mouse hearts 88 , and recently in a cardiac-specific Lmna D300N mouse model 74 .…”

Section: Discussionmentioning

confidence: 99%

Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells

Earle

Kirby

Fedorchak

et al. 2018

Preprint

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Mutations in the human LMNA gene, which encodes the nuclear envelope proteins lamins A and C, cause autosomal dominant Emery-Dreifuss muscular dystrophy, congenital muscular dystrophy, limb-girdle muscular dystrophy, and other diseases collectively known as laminopathies. The molecular mechanisms responsible for these diseases remain incompletely understood, but the muscle-specific defects suggest that mutations may render nuclei more susceptible to mechanical stress. Using three mouse models of muscle laminopathies, we found that Lmna mutations caused extensive nuclear envelope damage, consisting of chromatin protrusions and transient rupture of the nuclear envelope, in skeletal muscle cells in vitro and in vivo. The nuclear envelope damage was associated with progressive DNA damage, activation of DNA damage response pathways, and reduced viability. Intriguingly, nuclear envelope damage resulted from nuclear movement in maturing skeletal muscle cells, rather than actomyosin contractility, and was reversed by either depletion of kinesin-1 or stabilization of microtubules. Depletion of kinesin-1 also rescued DNA damage, indicating that DNA damage is the result of nuclear envelope damage. The extent of nuclear envelope damage and DNA damage in the different Lmna mouse models strongly correlated with the disease onset and severity in vivo, and inducing DNA damage in wild-type muscle cells was sufficient to phenocopy the reduced cell viability of lamin A/C-deficient muscle cells, suggesting a causative role of DNA damage in disease pathogenesis. Corroborating the mouse model data, muscle biopsies from patients with LMNA associated muscular dystrophy similarly revealed significant DNA damage compared to age-matched controls, particularly in severe cases of the disease. Taken together, these findings point to a new and important role of DNA damage as a pathogenic contributor for these skeletal muscle diseases.

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Section: Discussionmentioning

confidence: 99%

Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells

Earle

Kirby

Fedorchak

et al. 2018

Preprint

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“…The strength of this model is that the intersegmental muscle does not contain capillaries, satellite cells, endothelial cells or pericytes, meaning that all nuclei may be considered myonuclei 63 . However, the suggestion that the loss of 49% muscle mass within 3 days represents a model for the muscle mass loss during human aging over a period of 30 years would be too simplistic 12 . An alternative model of muscle fibre atrophy over a more prolonged period of time is cancer cachexia.…”

Section: Current Evidence From Animal Studiesmentioning

confidence: 99%

“…Based on the concept of the myonuclear domain theory, an approximate linear relationship must exist between total myonuclear number and muscle fibre size and/or volume. Although the myonuclear domain theory was quickly adopted by many investigators, it continues to be intensely debated within the field 7‐14 . For instance, based on the paradigm, the myonuclear domain should be kept (relatively) constant by adding additional nuclei (supplied by muscle satellite cells) during muscle fibre hypertrophy and by nuclear loss (through apoptosis) during muscle fibre atrophy 14 .…”

Section: Introductionmentioning

confidence: 99%

The concept of skeletal muscle memory: Evidence from animal and human studies

et al. 2020

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Within the current paradigm of the myonuclear domain theory, it is postulated that a linear relationship exists between muscle fibre size and myonuclear content. The myonuclear domain is kept (relatively) constant by adding additional nuclei (supplied by muscle satellite cells) during muscle fibre hypertrophy and nuclear loss (by apoptosis) during muscle fibre atrophy. However, data from recent animal studies suggest that myonuclei that are added to support muscle fibre hypertrophy are not lost within various muscle atrophy models. Such myonuclear permanence has been suggested to constitute a mechanism allowing the muscle fibre to (re)grow more efficiently during retraining, a phenomenon referred to as “muscle memory.” The concept of “muscle memory by myonuclear permanence” has mainly been based on data attained from rodent experimental models. Whether the postulated mechanism also holds true in humans remains largely ambiguous. Nevertheless, there are several studies in humans that provide evidence to potentially support or contradict (parts of) the muscle memory hypothesis. The goal of the present review was to discuss the evidence for the existence of “muscle memory” in both animal and human models of muscle fibre hypertrophy as well as atrophy. Furthermore, to provide additional insight in the potential presence of muscle memory by myonuclear permanence in humans, we present new data on previously performed exercise training studies. Finally, suggestions for future research are provided to establish whether muscle memory really exists in humans.

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“…Skeletal muscle fibers are syncytial in nature, containing hundreds of myonuclei positioned at the periphery of each myofiber in a non-random position, which minimizes transport distances between the nuclei themselves and the other regions of the myofiber [1,2]. Muscle fiber hypertrophy is accompanied by the addition of nuclei from stem cells, while the possible loss of nuclei following atrophy is still controversial [3]. In his seminal work, Spiro noted mispositioned myonuclei in a patient with myotubular myopathy, one of the central nuclear myopathies (CNM) [4].…”

Section: Introductionmentioning

confidence: 99%

Displaced Myonuclei in Cancer Cachexia Suggest Altered Innervation

Daou

Hassani

Matos

et al. 2020

IJMS

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An idiopathic myopathy characterized by central nuclei in muscle fibers, a hallmark of muscle regeneration, has been observed in cancer patients. In cancer cachexia skeletal muscle is incapable of regeneration, consequently, this observation remains unaccounted for. In C26-tumor bearing, cachectic mice, we observed muscle fibers with central nuclei in the absence of molecular markers of bona fide regeneration. These clustered, non-peripheral nuclei were present in NCAM-expressing muscle fibers. Since NCAM expression is upregulated in denervated myofibers, we searched for additional makers of denervation, including AchRs, MUSK, and HDAC. This last one being also consistently upregulated in cachectic muscles, correlated with an increase of central myonuclei. This held true in the musculature of patients suffering from gastrointestinal cancer, where a progressive increase in the number of central myonuclei was observed in weight stable and in cachectic patients, compared to healthy subjects. Based on all of the above, the presence of central myonuclei in cancer patients and animal models of cachexia is consistent with motor neuron loss or NMJ perturbation and could underlie a previously neglected phenomenon of denervation, rather than representing myofiber damage and regeneration in cachexia. Similarly to aging, denervation-dependent myofiber atrophy could contribute to muscle wasting in cancer cachexia.

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Skeletal Muscles Do Not Undergo Apoptosis During Either Atrophy or Programmed Cell Death-Revisiting the Myonuclear Domain Hypothesis

Cited by 58 publications

References 77 publications

Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells

Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells

The concept of skeletal muscle memory: Evidence from animal and human studies

Displaced Myonuclei in Cancer Cachexia Suggest Altered Innervation

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