Mitochondrial Transplantation Preserves Regenerative Capacity of Denervated Skeletal Muscle by Disrupting a Ca2+ Overload‐Mitophagy‐Ferroptosis Circuit
8 affiliations
- 1Department of Orthopedics Fuzhou University Affiliated Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University Fuzhou Fujian China
- 2Department of Orthopedics Ningde Clinical Medical College of Fujian Medical University Ningde Fujian China
- 3Fujian Provincial Clinical Medical Research Center for Spinal Nerve and Joint Diseases Fuzhou Fujian China
- 4Ningde Municipal Hospital Ningde Fujian China
- 5Clinical Medical Research Center of Provincial Hospital Affiliated to Fuzhou University Fuzhou China
- 6Institute of New Materials, Guangdong Academy of Sciences, State Key Laboratory of Special Materials Surface Engineering Guangzhou Guangdong China
- 7Guangdong‐Hong Kong Joint Laboratory of Modern Surface Engineering Technology, Guangdong Provincial Key Laboratory of Modern Surface Engineering Technology Guangzhou Guangdong China
- 8Engineering Research Center of Reactive Distillation, Fujian Province Higher Education Institutes, College of Chemical Engineering Fuzhou University Fuzhou Fujian China
Abstract
Background: Denervation‐induced muscle atrophy progresses during the interval between nerve injury and reinnervation, and depletion of muscle satellite cells (MuSCs) contributes to impaired functional recovery. Although mitochondrial dysfunction and impaired quality control are implicated in muscle wasting, whether excessive mitochondrial turnover drives MuSC failure after denervation remains unclear. This study aimed to identify the pathogenic mechanisms underlying MuSC depletion and determine whether mitochondrial transplantation therapy (MTT) preserves regenerative capacity.
Methods: A sciatic nerve transection model was established in mice to induce denervation‐associated muscle atrophy. Mitochondria isolated from differentiated MuSCs were transplanted into denervated gastrocnemius muscles beginning 6 h after injury and repeated every 3 days for 6 weeks. RNA sequencing, calcium imaging, mitochondrial ultrastructural analysis, mito‐mKeima‐based mitophagic flux assessment, flow cytometry and molecular analyses were performed to investigate disease mechanisms and therapeutic effects. In vitro calcium overload models combined with Mdivi‐1 treatment and Pink1 knockdown were used to define the regulatory pathway linking calcium stress, mitophagy and ferroptosis.
Results: Denervated muscle exhibited early calcium dyshomeostasis (Fluo‐4 AM fluorescence increased 6.7‐fold vs. Sham, p < 0.0001) and mitochondrial dysfunction within 3 days, followed by iron accumulation (nonheme iron increased 1.5‐fold, p = 0.0046) and ferroptotic changes by 2 weeks. Mechanistically, sustained calcium overload activated the Ampk‐Tsc2‐mTorc1 pathway in MuSCs, inducing Pink1‐dependent excessive mitophagic flux. Mito‐mKeima flow cytometry confirmed increased mitophagic flux after denervation, with approximately tenfold elevation at Day 3 and persistent activation at 2 weeks. Excessive mitophagy promoted Fth1 degradation (reduced by 47.5%, p = 0.0181) and increased Tfr1 expression (1.9‐fold, p = 0.0035), thereby enhancing ferroptotic susceptibility. Inhibition of mitochondrial fission or Pink1 knockdown reduced iron accumulation (Fe2+ fluorescence reduced by 58.3% and 69.2%, respectively, both p < 0.01) and protected MuSCs from ferroptosis. MTT restored mitochondrial homeostasis by reducing calcium overload (73.7% decrease vs. A23187, p < 0.0001), increasing ATP production (36.9%, p < 0.01), suppressing excessive mitophagic flux, normalizing iron metabolism (39.9% reduction, p = 0.0015) and preserving MuSCs (30.0% increase vs. DN_PBS, p = 0.0196). Consequently, MTT attenuated denervation‐induced muscle fibre atrophy and improved functional recovery following delayed nerve repair.
Conclusions: This study identifies an early pathogenic cascade linking calcium overload, excessive mitophagic flux and ferroptotic susceptibility as a critical driver of MuSC dysfunction during denervation‐induced muscle wasting. MTT preserves regenerative capacity by interrupting this degenerative circuit and restoring mitochondrial quality control, providing a potential therapeutic strategy for denervation‐associated muscle atrophy and other muscle wasting disorders.
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BibTeX
@article{ding2026mitochondrial,
title = {{Mitochondrial Transplantation Preserves Regenerative Capacity of Denervated Skeletal Muscle by Disrupting a Ca2+ Overload‐Mitophagy‐Ferroptosis Circuit}},
author = {Haiqi Ding and Jiagu Huang and Jiayao Zhang and Zhizhen He and Jun Luo and Zhao Lin and Linhai Yang and Yibin Su and Mingjuan Zhang and Fuli Wen and Yuan Lin and Cheng Chang and Hanhao Dai and Xuehui Ge and Jie Xu},
journal = {Journal of Cachexia, Sarcopenia and Muscle},
year = {2026},
month = nov,
doi = {10.1002/jcsm.70416},
url = {https://doi.org/10.1002/jcsm.70416},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Mitochondrial Transplantation Preserves Regenerative Capacity of Denervated Skeletal Muscle by Disrupting a Ca2+ Overload‐Mitophagy‐Ferroptosis Circuit
AU - Haiqi Ding
AU - Jiagu Huang
AU - Jiayao Zhang
AU - Zhizhen He
AU - Jun Luo
AU - Zhao Lin
AU - Linhai Yang
AU - Yibin Su
AU - Mingjuan Zhang
AU - Fuli Wen
AU - Yuan Lin
AU - Cheng Chang
AU - Hanhao Dai
AU - Xuehui Ge
AU - Jie Xu
PY - 2026
DA - 2026/11/05
JO - Journal of Cachexia, Sarcopenia and Muscle
DO - 10.1002/jcsm.70416
UR - https://doi.org/10.1002/jcsm.70416
AB - Background: Denervation‐induced muscle atrophy progresses during the interval between nerve injury and reinnervation, and depletion of muscle satellite cells (MuSCs) contributes to impaired functional recovery. Although mitochondrial dysfunction and impaired quality control are implicated in muscle wasting, whether excessive mitochondrial turnover drives MuSC failure after denervation remains unclear. This study aimed to identify the pathogenic mechanisms underlying MuSC depletion and determine whether mitochondrial transplantation therapy (MTT) preserves regenerative capacity. Methods: A sciatic nerve transection model was established in mice to induce denervation‐associated muscle atrophy. Mitochondria isolated from differentiated MuSCs were transplanted into denervated gastrocnemius muscles beginning 6 h after injury and repeated every 3 days for 6 weeks. RNA sequencing, calcium imaging, mitochondrial ultrastructural analysis, mito‐mKeima‐based mitophagic flux assessment, flow cytometry and molecular analyses were performed to investigate disease mechanisms and therapeutic effects. In vitro calcium overload models combined with Mdivi‐1 treatment and Pink1 knockdown were used to define the regulatory pathway linking calcium stress, mitophagy and ferroptosis. Results: Denervated muscle exhibited early calcium dyshomeostasis (Fluo‐4 AM fluorescence increased 6.7‐fold vs. Sham, p < 0.0001) and mitochondrial dysfunction within 3 days, followed by iron accumulation (nonheme iron increased 1.5‐fold, p = 0.0046) and ferroptotic changes by 2 weeks. Mechanistically, sustained calcium overload activated the Ampk‐Tsc2‐mTorc1 pathway in MuSCs, inducing Pink1‐dependent excessive mitophagic flux. Mito‐mKeima flow cytometry confirmed increased mitophagic flux after denervation, with approximately tenfold elevation at Day 3 and persistent activation at 2 weeks. Excessive mitophagy promoted Fth1 degradation (reduced by 47.5%, p = 0.0181) and increased Tfr1 expression (1.9‐fold, p = 0.0035), thereby enhancing ferroptotic susceptibility. Inhibition of mitochondrial fission or Pink1 knockdown reduced iron accumulation (Fe2+ fluorescence reduced by 58.3% and 69.2%, respectively, both p < 0.01) and protected MuSCs from ferroptosis. MTT restored mitochondrial homeostasis by reducing calcium overload (73.7% decrease vs. A23187, p < 0.0001), increasing ATP production (36.9%, p < 0.01), suppressing excessive mitophagic flux, normalizing iron metabolism (39.9% reduction, p = 0.0015) and preserving MuSCs (30.0% increase vs. DN_PBS, p = 0.0196). Consequently, MTT attenuated denervation‐induced muscle fibre atrophy and improved functional recovery following delayed nerve repair. Conclusions: This study identifies an early pathogenic cascade linking calcium overload, excessive mitophagic flux and ferroptotic susceptibility as a critical driver of MuSC dysfunction during denervation‐induced muscle wasting. MTT preserves regenerative capacity by interrupting this degenerative circuit and restoring mitochondrial quality control, providing a potential therapeutic strategy for denervation‐associated muscle atrophy and other muscle wasting disorders.
SN - 2190-5991
SN - 2190-6009
ER -