Resume: The benefits of resistance exercise may vary depending on the types of mutation associated with primary mitochondrial disease, a new study reports.
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Mitochondria serve as the main source of energy production in our cells, and resistance exercise is generally known to improve mitochondria function. However, the benefits of exercise in patients with primary mitochondrial diseases, which are heterogeneous and caused by a variety of genetic mutations, were largely unknown.
In a new study, researchers at Children’s Hospital of Philadelphia (CHOP) showed that the benefits of resistance exercise may vary depending on the type of mutation involved in mitochondrial disease, and while the benefits of exercise outweigh the risks, mitochondrial genetic status of patients should be taken into account when recommending exercise as therapy.
The findings were published online today by the Proceedings of the National Academy of Sciences.
Primary mitochondrial diseases represent the most prevalent inherited metabolic disorders, affecting approximately 1 in 4,200 people. These disorders can be caused by hundreds of different mutations in nuclear DNA (DNA inside our cells) or mitochondrial DNA (mtDNA or the DNA inside the mitochondria inside our cells).
Universal treatments for these patients are limited. However, resistance exercise has been shown to improve mitochondrial function in healthy people and reduce the risk of developing secondary metabolic disorders such as diabetes or neurodegenerative disorders.
However, these recommendations were based on healthy people without primary mitochondrial disease. Therefore, the researchers wanted to determine the effectiveness for these patients and whether they actually benefit from resistance exercise.
“There was no consensus among clinicians who care for patients with mitochondrial disease about whether resistance exercise actually offers benefits,” said Patrick Schaefer, Ph.D., a postdoctoral fellow in CHOP’s Center for Mitochondrial and Epigenomic Medicine and first author of the study. .
“Exercise helps create more mitochondria, but if those mitochondria still have the mutations associated with primary mitochondrial disease, there is a possibility that exercise could put some patients at risk.”
Due to the heterogeneity of primary mitochondrial disease among patients, the researchers used animal models to study five mutations responsible for the disease.
The aim of the study was to determine the relationship between mitochondrial mutations, resistance exercise response and underlying molecular pathways in these models with different mitochondrial mutations.
The study found that endurance exercise had different impacts on the models depending on the mutation involved. Exercise improved response in the model with the mtDNA ND6 mutation in complex I.
The model with a CO1 mutation affecting complex IV showed significantly fewer positive effects related to exercise, and the model with a ND5 complex 1 mutation did not respond to exercise at all. In the model that was deficient in nuclear DNA Ant1, resistance exercise actually worsened the cardiomyopathy.
In addition, the researchers were able to correlate the gene expression profile of heart and skeletal muscle in the model with exercise response and identified oxidative phosphorylation, amino acid metabolism, and cell cycle regulation as key pathways in exercise response. , suggesting how the model could be adapted. to study responses to exercise in humans with primary mitochondrial disease.
Despite the mixed responses from the models used in this study, the authors note that the benefits of exercise outweigh the risks in most cases. However, the physical and mitochondrial status of the patient must be taken into account when recommending therapeutic exercises.
Additionally, the study could help researchers identify biomarkers and pathways to help predict mitochondrial response to exercise in both mitochondrial patients and the healthy population harboring different mitochondrial haplogroups.
“This work is critically important in showing that people with different mitochondrial bioenergetics will respond differently to endurance exercise,” said study senior author Douglas C. Wallace, Ph.D., director of the Center for Mitochondrial Medicine and CHOP Epigenomics and the Michael and Charles Barnett Chair in Pediatric Mitochondrial Medicine and Metabolic Diseases.
“This is of great relevance to people ranging from athletes to mitochondrial disease patients and everyone in between.”
About this research news in genetics and exercise
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“Mitochondrial mutations alter resistance exercise response and determinants in miceby Patrick M. Schaefer et al. PNAS
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Mitochondrial mutations alter resistance exercise response and determinants in mice
Primary mitochondrial diseases (PMDs) are a heterogeneous group of metabolic disorders that can be caused by hundreds of mutations in mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) genes. Current therapeutic approaches are limited, although one approach has been physical training.
Resistance exercise is known to improve mitochondrial function in healthy subjects and reduce the risk of secondary metabolic disorders such as diabetes or neurodegenerative disorders. However, in premenstrual syndromes, the benefit of resistance exercise is unclear, and exercise might be beneficial for some mitochondrial disorders but contraindicated in others.
Here we investigate the effect of an endurance exercise regimen in mouse models for PMD harboring distinct mitochondrial mutations.
We show that while an ND6 mtDNA mutation in complex I demonstrated an enhanced response to exercise, mice with a CO1 mutation affecting complex IV showed significantly fewer positive effects, and mice with a complex I mutation of ND5 did not respond to exercise at all. For mice deficient in the nDNA adenine nucleotide translocase 1 (Ant1), resistance exercise actually worsened dilated cardiomyopathy.
Correlation of heart and skeletal muscle gene expression profiling with physiological response to exercise identified oxidative phosphorylation, amino acid metabolism, matrosome (extracellular matrix [ECM]) the structure and regulation of the cell cycle as key pathways in the response to exercise. This emphasizes the crucial role of mitochondria in determining exercise capacity and response to exercise.
Consequently, the benefit of resistance exercise in premenstrual syndromes is highly dependent on the underlying mutation, although our results suggest an overall beneficial effect.
