NuMA1 controls myonuclear motility in striated skeletal muscle through AMPK activity and is impaired in Duchenne muscular dystrophy
Abstract
Skeletal muscle consists of a bundle of thousands of post-mitotic multinucleated cells (i.e., myofibers), in which myonuclei are evenly spaced and positioned at the periphery. This myonuclear positioning shapes myonuclear domain (MND) in myofibers, is essential for the transcriptional integrity of myofibers, is driven by the cytoskeleton and associated proteins and is required for proper myofiber functions. In numerous muscle diseases (i.e., myopathies), alteration of myonuclei localization contributes to myofiber dysfunction, supporting the need to better understand the fundamental mechanisms that regulate myonuclei dynamics in differentiated myofibers. In this study, we show that in Duchenne muscular dystrophy (DMD) myofibers, myonuclei are more dynamic and contribute to the failure in MND settings, suggesting enhanced myonuclear motility impacts myonuclear distribution. To identify new actors in MND settings, we performed a mass spectrometry (MS)-based proteomic analysis to identify microtubule-associated proteins (MAPs) in myotubes/myofibers and performed a siRNA screening on candidates. This approach highlighted NuMA1 as a new factor controlling myoblast fusion and myonuclear positioning through the control of nuclear-microtubule-organizing-center (n-MTOC) integrity and microtubule network orientation. Strikingly, while NuMA1 is restrained to myonuclei in mononucleated myoblasts, it progressively accumulates in the cytoplasm during muscle cell differentiation, preferentially with microtubule (MT) nucleation spots at the vicinity of the nuclear membrane. We identified that AMP Kinase activity has an essential role in NuMA1 nuclear/cytoplasmic accumulation through the specific phosphorylation on serine-1853 and the ability of myonuclei to accumulate NuMA1 is correlated to their motility in myofibers. Finally, we show that nuclear NuMA1 content is increased in DMD patients and mdx mouse model, contributing to more dynamic myonuclei that can be manipulated pharmacologically through the control of AMPK activity. Altogether, our data identifies a novel mechanism by which nuclear sequestration of a MAP allows to couple nuclear positioning and motion to MT organization along skeletal muscle differentiation.
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BibTeX
@article{couturier2026numa1,
title = {{NuMA1 controls myonuclear motility in striated skeletal muscle through AMPK activity and is impaired in Duchenne muscular dystrophy}},
author = {Nathalie Couturier and Léa Castellano and Alireza Ghasemizadeh and Emilie Christin and Muriel Sébastien and Caroline Brun and Damien Caillol and Céline Malleval and Alexandre Janin and Gaëtan Juban and Alexis Osseni and Jean-Luc Thomas and Stéphane Koenig and Jessica Brunetti and Alexandra Kraut and Yohann Couté and Nathalie Streichenberger and Rémi Mounier and Vincent Gache},
journal = {Cell Death and Disease},
year = {2026},
month = oct,
doi = {10.1038/s41419-026-08987-5},
url = {https://hal.science/hal-05747680v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - NuMA1 controls myonuclear motility in striated skeletal muscle through AMPK activity and is impaired in Duchenne muscular dystrophy
AU - Nathalie Couturier
AU - Léa Castellano
AU - Alireza Ghasemizadeh
AU - Emilie Christin
AU - Muriel Sébastien
AU - Caroline Brun
AU - Damien Caillol
AU - Céline Malleval
AU - Alexandre Janin
AU - Gaëtan Juban
AU - Alexis Osseni
AU - Jean-Luc Thomas
AU - Stéphane Koenig
AU - Jessica Brunetti
AU - Alexandra Kraut
AU - Yohann Couté
AU - Nathalie Streichenberger
AU - Rémi Mounier
AU - Vincent Gache
PY - 2026
DA - 2026/10/13
JO - Cell Death and Disease
DO - 10.1038/s41419-026-08987-5
UR - https://hal.science/hal-05747680v1
AB - Skeletal muscle consists of a bundle of thousands of post-mitotic multinucleated cells (i.e., myofibers), in which myonuclei are evenly spaced and positioned at the periphery. This myonuclear positioning shapes myonuclear domain (MND) in myofibers, is essential for the transcriptional integrity of myofibers, is driven by the cytoskeleton and associated proteins and is required for proper myofiber functions. In numerous muscle diseases (i.e., myopathies), alteration of myonuclei localization contributes to myofiber dysfunction, supporting the need to better understand the fundamental mechanisms that regulate myonuclei dynamics in differentiated myofibers. In this study, we show that in Duchenne muscular dystrophy (DMD) myofibers, myonuclei are more dynamic and contribute to the failure in MND settings, suggesting enhanced myonuclear motility impacts myonuclear distribution. To identify new actors in MND settings, we performed a mass spectrometry (MS)-based proteomic analysis to identify microtubule-associated proteins (MAPs) in myotubes/myofibers and performed a siRNA screening on candidates. This approach highlighted NuMA1 as a new factor controlling myoblast fusion and myonuclear positioning through the control of nuclear-microtubule-organizing-center (n-MTOC) integrity and microtubule network orientation. Strikingly, while NuMA1 is restrained to myonuclei in mononucleated myoblasts, it progressively accumulates in the cytoplasm during muscle cell differentiation, preferentially with microtubule (MT) nucleation spots at the vicinity of the nuclear membrane. We identified that AMP Kinase activity has an essential role in NuMA1 nuclear/cytoplasmic accumulation through the specific phosphorylation on serine-1853 and the ability of myonuclei to accumulate NuMA1 is correlated to their motility in myofibers. Finally, we show that nuclear NuMA1 content is increased in DMD patients and mdx mouse model, contributing to more dynamic myonuclei that can be manipulated pharmacologically through the control of AMPK activity. Altogether, our data identifies a novel mechanism by which nuclear sequestration of a MAP allows to couple nuclear positioning and motion to MT organization along skeletal muscle differentiation.
SN - 2041-4889
ER -