Recovery from impaired muscle growth arises from prolonged postnatal accretion of myonuclei in Atrx mutant mice.

Michael S Huh,Kevin G Young,Keqin Yan,Tina Price-O’Dea,David J Picketts,Gerhard Wiche

doi:10.1371/journal.pone.0186989

Michael S Huh, Kevin G Young + Show 4 more

Open Access

https://doi.org/10.1371/journal.pone.0186989

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Journal: PloS one	Publication Date: Nov 2, 2017
Citations: 8	License type: CC BY 4.0

Affiliation: Ottawa Hospital, University of Ottawa

Abstract

Reduced muscle mass due to pathological development can occur through several mechanisms, including the loss or reduced proliferation of muscle stem cells. Muscle-specific ablation of the α-thalassemia mental retardation syndrome mutant protein, Atrx, in transgenic mice results in animals with a severely reduced muscle mass at three weeks of age; yet this muscle mass reduction resolves by adult age. Here, we explore the cellular mechanism underlying this effect. Analysis of Atrx mutant mice included testing for grip strength and rotorod performance. Muscle fiber length, fiber volume and numbers of myofiber-associated nuclei were determined from individual EDL or soleus myofibers isolated at three, five, or eight weeks. Myofibers from three week old Atrx mutant mice are smaller with fewer myofiber-associated nuclei and reduced volume compared to control animals, despite similar fiber numbers. Nonetheless, the grip strength of Atrx mutant mice was comparable to control mice when adjusted for body weight. Myofiber volume remained smaller at five weeks, becoming comparable to controls by 8 weeks of age. Concomitantly, increased numbers of myofiber-associated nuclei and Ki67+ myoblasts indicated that the recovery of muscle mass likely arises from the prolonged accretion of new myonuclei. This suggests that under disease conditions the muscle satellite stem cell niche can remain in a prolonged active state, allowing for the addition of a minimum number of myonuclei required to achieve a normal muscle size.

Highlights

The postnatal growth of skeletal muscle encountering experimental overload hypertrophy or following exercise requires the contribution of new myoblast nuclei to the muscle fiber syncytium to allow for an increase in fiber size [1,2,3]
Many patients display hypotonia at birth, have delayed ambulation and kyphosis. While these features of the disease are often attributed to a CNS defect, our characterization of muscle-specific Atrx conditional knockout mice has indicated that these muscle deficiencies may result from a combination of CNS and skeletal muscle defects [5]
Atrx conditional knockout (cKO) mice have reduced muscle mass but equivalent grip strength To further our understanding of the role of Atrx in tissue development, two mouse models have been generated; a conditional allele that results in protein ablation when bred to specific Cre driver lines and a hypomorphic mutation that mimics a human mutation in exon 2 producing reduced levels of an N-terminally truncated protein [15, 16]

Summary

Introduction

The postnatal growth of skeletal muscle encountering experimental overload hypertrophy or following exercise requires the contribution of new myoblast nuclei to the muscle fiber syncytium to allow for an increase in fiber size [1,2,3]. The production of myoblasts, derived from the muscle satellite cell niche, requires the coordinated expression of multiple genes which restrict the lineage potential of the cells and initiate the expression of muscle-specific proteins. Our previous work has demonstrated an important role for the Atrx chromatin remodeling protein in postnatal myoblast production [5]. Many patients display hypotonia at birth, have delayed ambulation and kyphosis. While these features of the disease are often attributed to a CNS defect, our characterization of muscle-specific Atrx conditional knockout (cKO) mice has indicated that these muscle deficiencies may result from a combination of CNS and skeletal muscle defects [5]

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