Gene shifting: a novel therapy for mitochondrial myopathy

Taivassalo, T

doi:10.1093/hmg/8.6.1047

Cited by 160Mitochondrial Function and PathologyMuscle Physiology and DisordersAmyotrophic Lateral Sclerosis Research

Gene shifting: a novel therapy for mitochondrial myopathy

Taivassalo, T·1999·Human Molecular Genetics

DOI 10.1093/hmg/8.6.1047

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Abstract

Mutations in mitochondrial DNA (mtDNA) are the most frequent causes of mitochondrial myopathy in adults. In the majority of cases mutant and wild-type mtDNAs coexist, a condition referred to as mtDNA heteroplasmy; however, the relative frequency of each species varies widely in different cells and tissues. Nearly complete segregation of mutant and wild-type mtDNAs has been observed in the skeletal muscle of many patients. In such patients mutant mtDNAs pre-dominate in mature myofibers but are rare or undetectable in skeletal muscle satellite cells cultured in vitro. This pattern is thought to result from positive selection for the mutant mtDNA in post-mitotic myofibers and loss of the mutant by genetic drift in satellite cells. Satellite cells are dormant myoblasts that can be stimulated to re-enter the cell cycle and fuse with existing myofibers in response to signals for muscle growth or repair. We tested whether we could normalize the mtDNA genotype in mature myofibers in a patient with mitochondrial myopathy by enhancing the incorporation of satellite cells through regeneration following injury or muscle hypertrophy, induced by either eccentric or concentric resistance exercise training. We show a remarkable increase in the ratio of wild-type to mutant mtDNAs, in the proportion of muscle fibers with normal respiratory chain activity and in muscle fiber cross-sectional area after a short period of concentric exercise training. These data show that it is possible to reverse the molecular events that led to expression of metabolic myopathy and demonstrate the effectiveness of this form of 'gene shifting' therapy.

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Resistance training in a patient with the G12315A tRNAleu(CUN) point mutation significantly improved heteroplasmic ratios and increased the number of respiratory-competent fibers in muscle fibers.
“This activation is accomplished with either eccentric or concentric resistance exercise, as shown in a patient with the G12315A tRNAleu(CUN) point mutation, where resistance training significantly improved heteroplasmic ratios and increased the number of respiratory-competent fibers in muscle fibers (Taivassalo et al., 1999).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Taivassalo et al., 1999

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myopathy
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Authors: Taivassalo, T.
Affiliations: Montreal Neurological Institute and Hospital (CA)
Corresponding author: Taivassalo, T
ORCID: Taivassalo, T
Venue: Human Molecular Genetics
Publisher: Oxford University Press (OUP)
Published: 1999-06-01
Volume: 8
Issue: 6
Pages: 1047-1052
ISSN: 0964-6906 (ISSN-L)
1460-2083
DOI: 10.1093/hmg/8.6.1047
OpenAlex: W2151218248
Cited by: 160
References: 25
Citations by year: 2026: 2 · 2025: 2 · 2023: 2 · 2022: 2 · 2021: 8 · 2020: 2 · 2019: 8 · 2018: 2 · 2017: 2 · 2016: 9 · 2015: 3 · 2014: 3 · 2013: 4 · 2012: 6
FWCI: 2.64
Type: journal article
Language: en
Open access: closed
Locations: Human Molecular Genetics (publishedVersion)
PubMed (publishedVersion)
HighWire Press Open Archive (submittedVersion)
Funders: Muscular Dystrophy Association
Killam Trusts
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords: mitochondrial myopathy, mitochondrial heteroplasmy, mitochondrial DNA mutations, skeletal muscle satellite cells, myofiber regeneration, resistance training, concentric exercise, eccentric exercise, muscle fiber cross-sectional area, respiratory chain activity, metabolic myopathies, genetic drift
MeSH terms: Creatine Kinase, DNA, Mitochondrial, Exercise Therapy, Gene Expression Regulation, Genotype, Humans, Male, Middle Aged, Muscle Contraction, Mutation, Phenotype, RNA, Transfer, Leu, Mitochondrial Myopathies, Muscle, Skeletal

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Gene shifting: a novel therapy for mitochondrial myopathy

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