Myopathy reversion in mice after restauration of mitochondrial complex I

Claudia V. Pereira, Susana Peralta, Tania Arguello, Sandra R. Bacman, Francisca Diaz, Carlos T. Moraes

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Myopathies are common manifestations of mitochondrial diseases. To investigate whether gene replacement can be used as an effective strategy to treat or cure mitochondrial myopathies, we have generated a complex I conditional knockout mouse model lacking NDUFS3 subunit in skeletal muscle. NDUFS3 protein levels were undetectable in muscle of 15-day-old smKO mice, and myopathy symptoms could be detected by 2 months of age, worsening over time. rAAV9-Ndufs3 delivered systemically into 15- to 18-day-old mice effectively restored NDUFS3 levels in skeletal muscle, precluding the development of the myopathy. To test the ability of rAAV9-mediated gene replacement to revert muscle function after disease onset, we also treated post-symptomatic, 2-month-old mice. The injected mice showed a remarkable improvement of the mitochondrial myopathy and biochemical parameters, which remained for the duration of the study. Our results showed that muscle pathology could be reversed after restoring complex I, which was absent for more than 2 months. These findings have far-reaching implications for the ability of muscle to tolerate a mitochondrial defect and for the treatment of mitochondrial myopathies.

Original languageEnglish (US)
Article numbere10674
JournalEMBO Molecular Medicine
Issue number2
StatePublished - Feb 7 2020


  • NDUFS3
  • adeno-associated virus
  • complex I
  • gene therapy
  • mitochondrial myopathies

ASJC Scopus subject areas

  • Molecular Medicine


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