mtDNA alterations in muscle progenitors determine myoblast differentiation and disrupt skeletal muscle architecture
Abstract
Mitochondrial DNA (mtDNA) damage has been linked to age-related tissue decline, yet its impact on muscle stem cells (MuSCs) integrity remains unclear. Here, we used a dominant-negative variant of the mitochondrial helicase Twinkle (p.K320E) to induce mtDNA instability in C2C12 and MuSCs, and examined myogenic differentiation. In C2C12, mtDNA alterations impaired respiratory complex assembly, increased reactive oxygen species, and disrupted differentiation. Proteomic analyses of differentiated C2C12 revealed extensive remodeling of the mitochondrial proteome. In vivo, during muscle regeneration, MuSCs expressing K320E generated fibers showing mitochondrial dysfunction and elevated oxidative stress. Furthermore, when mtDNA instability was induced during early postnatal stages, mtDNA alterations were progressively transmitted to mature myofibers, resulting in persistent fiber remodeling of the skeletal muscle. Together, these findings identify mtDNA instability in muscle progenitors as a driver of skeletal muscle remodeling and reveal that even modest levels of mtDNA alterations are sufficient to compromise skeletal muscle function.
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BibTeX
@article{sen2026mtdna,
title = {{mtDNA alterations in muscle progenitors determine myoblast differentiation and disrupt skeletal muscle architecture}},
author = {Ayesha Sen and Olivier Baris and Yulia Schaumkessel and Sebastian Kallabis and Claudie Gabillard-Lefort and Valerie Desquiret and Rudolf Wiesner and David Pla-Martín},
journal = {Cell Reports},
year = {2026},
month = oct,
doi = {10.1016/j.celrep.2026.117979},
url = {https://hal.science/hal-05798800v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - mtDNA alterations in muscle progenitors determine myoblast differentiation and disrupt skeletal muscle architecture
AU - Ayesha Sen
AU - Olivier Baris
AU - Yulia Schaumkessel
AU - Sebastian Kallabis
AU - Claudie Gabillard-Lefort
AU - Valerie Desquiret
AU - Rudolf Wiesner
AU - David Pla-Martín
PY - 2026
DA - 2026/10/14
JO - Cell Reports
DO - 10.1016/j.celrep.2026.117979
UR - https://hal.science/hal-05798800v1
AB - Mitochondrial DNA (mtDNA) damage has been linked to age-related tissue decline, yet its impact on muscle stem cells (MuSCs) integrity remains unclear. Here, we used a dominant-negative variant of the mitochondrial helicase Twinkle (p.K320E) to induce mtDNA instability in C2C12 and MuSCs, and examined myogenic differentiation. In C2C12, mtDNA alterations impaired respiratory complex assembly, increased reactive oxygen species, and disrupted differentiation. Proteomic analyses of differentiated C2C12 revealed extensive remodeling of the mitochondrial proteome. In vivo, during muscle regeneration, MuSCs expressing K320E generated fibers showing mitochondrial dysfunction and elevated oxidative stress. Furthermore, when mtDNA instability was induced during early postnatal stages, mtDNA alterations were progressively transmitted to mature myofibers, resulting in persistent fiber remodeling of the skeletal muscle. Together, these findings identify mtDNA instability in muscle progenitors as a driver of skeletal muscle remodeling and reveal that even modest levels of mtDNA alterations are sufficient to compromise skeletal muscle function.
SN - 2211-1247
SN - 2211-1247
ER -