Human Growth — Methods of Approach

Cheek, Donald B.

doi:10.1111/j.1440-1754.1977.tb01129.x

Cited by 3 publications

(3 citation statements)

References 27 publications

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“…The minimum telomere repeat length decreases continuously from ~ 12 to ~ 8 telomere restriction fragments (equivalent to some 45 cell divisions) between birth and adulthood . This is fully consistent with the operation of serial asymmetric cell divisions to account for the 10–15‐fold increase in muscle nuclear content between birth and adulthood .…”

Section: Mouse and Humans Grow In Different Wayssupporting

confidence: 73%

The mdx mouse model as a surrogate forDuchenne muscular dystrophy

2013

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Research into fundamental principles and the testing of therapeutic hypotheses for treatment of human disease is commonly conducted on mouse models of human diseases. Although this is often the only practicable approach, it carries a number of caveats arising from differences between the two species. This article is centred on the example of skeletal muscle disease, in particular muscular dystrophy, to identify some of the principal classes of obstacle to the translation of data from mouse to man. Of these, the difference in scale is one of the most commonly ignored and is of particular interest because it has quite major repercussions for evaluation of some classes of intervention and of assessment criteria while having comparatively little bearing on others. Likewise, interspecies differences and similarities in cell and molecular biological mechanisms underlying development, growth and response to pathological processes should be considered on an individual basis. An awareness of such distinctions is crucial if we are to avoid misjudgement of the likely efficacy in man of results obtained on mouse models.

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Section: Mouse and Humans Grow In Different Wayssupporting

confidence: 73%

The mdx mouse model as a surrogate forDuchenne muscular dystrophy

2013

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“…Satellite cell-dependent growth in the mouse ceases at 3 weeks, coincident with the onset of myonecrosis and regeneration, with no overlap between the separate programmes followed by satellite cells undertaking these two activities [ 29 ]. By contrast, in growing boys, myogenic cell proliferation continues throughout the juvenile and pubertal periods [ 30 , 31 ], presenting every prospect of adverse interference in DMD boys between the separate growth and regeneration programmes. Thus, some benefit might be achieved by blockade of discrepant signals between these two different satellite cell functions.…”

Section: Discussionmentioning

confidence: 99%

Muscular dystrophy in the mdx mouse is a severe myopathy compounded by hypotrophy, hypertrophy and hyperplasia

et al. 2015

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BackgroundPreclinical testing of potential therapies for Duchenne muscular dystrophy (DMD) is conducted predominantly of the mdx mouse. But lack of a detailed quantitative description of the pathology of this animal limits our ability to evaluate the effectiveness of putative therapies or their relevance to DMD.MethodsAccordingly, we have measured the main cellular components of muscle growth and regeneration over the period of postnatal growth and early pathology in mdx and wild-type (WT) mice; phalloidin binding is used as a measure of fibre size, myonuclear counts and BrdU labelling as records of myogenic activity.ResultsWe confirm a two-phase postnatal growth pattern in WT muscle: first, increase in myonuclear number over weeks 1 to 3, then expansion of myonuclear domain. Mdx muscle growth lags behind that of WT prior to overt signs of pathology. Fibres are smaller, with fewer myonuclei and smaller myonuclear domains. Moreover, satellite cells are more readily detached from mdx than WT muscle fibres. At 3 weeks, mdx muscles enter a phase of florid myonecrosis, accompanied by concurrent regeneration of an intensity that results in complete replacement of pre-existing muscle over the succeeding 3 to 4 weeks.Both WT and mdx muscles attain maximum size by 12 to 14 weeks, mdx muscle fibres being up to 50% larger than those of WT as they become increasingly branched. Mdx muscle fibres also become hypernucleated, containing twice as many myonuclei per sarcoplasmic volume, as those of WT, the excess corresponding to the number of centrally placed myonuclei.ConclusionsThe best-known consequence of lack of dystrophin that is common to DMD and the mdx mouse is the conspicuous necrosis and regeneration of muscle fibres. We present protocols for measuring this in terms both of loss of muscle nuclei previously labelled with BrdU and of the intensity of myonuclear labelling with BrdU administered during the regeneration period. Both measurements can be used to assess the efficacy of putative antinecrotic agents. We also show that lack of dystrophin is associated with a number of previously unsuspected abnormalities of muscle fibre structure and function that do not appear to be directly associated with myonecrosis.

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“…Relating the age of a mouse to a human is quite difficult, but it has been suggested that a 9 day old mouse is equivalent to a 1 year old child [ 28 ]. In the human, skeletal muscle mass increases throughout adolescence [ 29 ] to a far greater extent than in rats [ 30 ]. Hansson et al [ 25 ] showed that the number of myonuclei in myofibres scaled sublinearly to cell volume, but close to linear with cell surface and this was similar in growing mouse muscles and in adult mouse and human muscles.…”

Section: Human Compared To Rodent Skeletal Muscle Growthmentioning

confidence: 99%

Changes in Myonuclear Number During Postnatal Growth – Implications for AAV Gene Therapy for Muscular Dystrophy

Morgan

Muntoni

2021

JND

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Adult skeletal muscle is a relatively stable tissue, as the multinucleated muscle fibres contain post-mitotic myonuclei. During early postnatal life, muscle growth occurs by the addition of skeletal muscle stem cells (satellite cells) or their progeny to growing muscle fibres. In Duchenne muscular dystrophy, which we shall use as an example of muscular dystrophies, the muscle fibres lack dystrophin and undergo necrosis. Satellite-cell mediated regeneration occurs, to repair and replace the necrotic muscle fibres, but as the regenerated muscle fibres still lack dystrophin, they undergo further cycles of degeneration and regeneration. AAV gene therapy is a promising approach for treating Duchenne muscular dystrophy. But for a single dose of, for example, AAV coding for dystrophin, to be effective, the treated myonuclei must persist, produce sufficient dystrophin and a sufficient number of nuclei must be targeted. This latter point is crucial as AAV vector remains episomal and does not replicate in dividing cells. Here, we describe and compare the growth of skeletal muscle in rodents and in humans and discuss the evidence that myofibre necrosis and regeneration leads to the loss of viral genomes within skeletal muscle. In addition, muscle growth is expected to lead to the dilution of the transduced nuclei especially in case of very early intervention, but it is not clear if growth could result in insufficient dystrophin to prevent muscle fibre breakdown. This should be the focus of future studies.

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Human Growth — Methods of Approach

Cited by 3 publications

References 27 publications

The mdx mouse model as a surrogate forDuchenne muscular dystrophy

The mdx mouse model as a surrogate forDuchenne muscular dystrophy

Muscular dystrophy in the mdx mouse is a severe myopathy compounded by hypotrophy, hypertrophy and hyperplasia

Changes in Myonuclear Number During Postnatal Growth – Implications for AAV Gene Therapy for Muscular Dystrophy

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