Prelamin A causes aberrant myonuclear arrangement and results in muscle fiber weakness.

Yotam Levy,Yueh-Mei Hsu,Carlos Lopez-Otin,Stephen D.R Harridge,Brian K Kennedy,Elizabeth M Mcnally,Manfred Alsheimer,Chen-Yu Liao,Dawn A Lowe,Vladimir A Snetkov,Yaiza Español,Stephen G Young,Loren G Fong,Jacob A Ross,Julien Ochala,Steven Lynham,Megan J Puckelwartz,Marili Niglas

doi:10.1172/jci.insight.120920

Abstract

Physiological and premature aging are frequently associated with an accumulation of prelamin A, a precursor of lamin A, in the nuclear envelope of various cell types. Here, we aimed to underpin the hitherto unknown mechanisms by which prelamin A alters myonuclear organization and muscle fiber function. By experimentally studying membrane-permeabilized myofibers from various transgenic mouse lines, our results indicate that, in the presence of prelamin A, the abundance of nuclei and myosin content is markedly reduced within muscle fibers. This leads to a concept by which the remaining myonuclei are very distant from each other and are pushed to function beyond their maximum cytoplasmic capacity, ultimately inducing muscle fiber weakness.

Highlights

Biological aging involves complex dysfunctional cellular processes with unclear underlying mechanisms, including a potential involvement of alterations at the nuclear level in a wide range of tissues [1]
Our data showed that the overall number of nuclei per millimeter fiber length was significantly lower in mice lacking Zmpste24 than in WT animals (Figure 2B)
The content of myosin and total contractile proteins was lower in myofibers from mice lacking Zmpste24 when compared with fibers from WT mice, and this was dependent on fiber size, with a greater effect observed in fibers with larger cross-sectional area (Figure 4). Together these results suggest that mechanisms related to (i) myonuclear number and (ii) contractile protein content are likely to be involved in the etiology of muscle fiber dysfunction in the presence of prelamin A

Summary

Introduction

Biological aging involves complex dysfunctional cellular processes with unclear underlying mechanisms, including a potential involvement of alterations at the nuclear level in a wide range of tissues [1]. Each of them controls protein synthesis in a defined volume of cytoplasm termed the myonuclear domain (MND). Regular positioning of these nuclei is essential for optimal nuclear cooperation, MND size, and efficient regulation and distribution of gene products [6]. We tested the hypothesis that an accumulation of prelamin A would alter nuclear number and positioning, disrupting the ability of fibers to generate force. We used various transgenic mouse models that mimic premature aging syndromes, wherein the composition of nuclear envelope proteins is altered. We isolated and membrane-permeabilized individual muscle fibers, ran a series of contractile and morphological analyses, including an evaluation of the 3D organization of nuclei, using our image analysis algorithm applied to reconstructed confocal images [7]

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Conclusion