Summary: The benefits of endurance exercise may vary depending on the types of mutations associated with primary mitochondrial disease, a new study reports.
Mitochondria are the primary source of energy production in our cells, and endurance exercise is generally known to improve mitochondrial function. However, the benefits of exercise in patients with primary mitochondrial diseases, which are heterogeneous and caused by various genetic mutations, were largely unknown.
In a new study, researchers from the Children’s Hospital of Philadelphia (CHOP) have demonstrated that the benefits of endurance exercise may vary depending on the type of mutation involved in mitochondrial disease, and although the benefits of exercise outweigh the risks, the mitochondrial genetic status of patients should be considered when recommending exercise as therapy.
The results were published online today by the Proceedings of the National Academy of Sciences.
Primary mitochondrial diseases are the most common inherited metabolic disorders, affecting approximately 1 in 4,200 people. These disorders can be caused by hundreds of different mutations in nuclear DNA (DNA in our cells) or mitochondrial DNA (mtDNA , or the DNA in the mitochondria in our cells).
Universal treatments for these patients are limited. However, endurance exercise has been shown to improve mitochondrial function in healthy people and reduce the risk of developing secondary metabolic disorders like 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 benefited from endurance exercise.
“There was no consensus among clinicians who see patients with mitochondrial disease about whether endurance exercise really provides benefits,” said Patrick Schaefer, Ph.D., postdoctoral fellow at the Center for mitochondrial and epigenomic medicine of CHOP and first author of the study. .
“Exercise helps create more mitochondria, but if those mitochondria still have the mutations associated with primary mitochondrial disease, exercise may put some patients at risk.”
Due to the heterogeneity of primary mitochondrial disease among patients, researchers used animal models to study five disease-causing mutations.
The aim of the study was to determine the relationship between mitochondrial mutations, response to endurance exercise, and underlying molecular pathways in those models with distinct mitochondrial mutations.
The study found that endurance exercise had different impacts on patterns depending on the mutation involved. Exercise improved the response in the model with the mtDNA mutation ND6 in complex I.
The model with a CO1 mutation affecting complex IV showed significantly fewer positive exercise-related effects, and the model with a complex 1 ND5 mutation did not respond to exercise at all. In the Ant1 nuclear DNA-deficient model, endurance exercise actually worsened cardiomyopathy.
Additionally, the researchers were able to correlate the gene expression profile of skeletal muscle and heart in the model with response to exercise and identified oxidative phosphorylation, amino acid metabolism, and cell cycle regulation as key pathways in response to exercise, suggesting how the model might be adapted. to study exercise responses 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 state of the patient should be considered 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 of fundamental importance in demonstrating that individuals with different mitochondrial bioenergetics will respond differently to endurance exercise,” said study lead author Douglas C. Wallace, Ph.D. from the Center for Mitochondrial Medicine and Epigenomics at CHOP and the Michael and Charles Barnett Endowed Chair in Pediatric Mitochondrial Medicine and Metabolic Diseases.
“This is of great relevance to individuals ranging from athletes to patients with mitochondrial disease, and everyone in between.”
About This Genetics and Exercise Research News
Original research: Access closed.
“Mitochondrial mutations alter endurance exercise response and determinants in mice” by Patrick M. Schaefer et al. PNAS
Mitochondrial mutations alter endurance 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.
Endurance 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 PMD, the benefit of endurance 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 PMDs harboring distinct mitochondrial mutations.
We show that while an ND6 mtDNA mutation in complex I demonstrated an improvement in response to exercise, mice with a CO1 mutation affecting complex IV showed significantly less positive effects, and mice with an ND5 complex I mutation did not respond to exercise at all. For mice deficient in nDNA adenine nucleotide translocase 1 (Ant1), endurance exercise actually worsened dilated cardiomyopathy.
Correlation of skeletal muscle and heart gene expression profile with physiological response to exercise identified oxidative phosphorylation, amino acid metabolism, matrisome (extracellular matrix [ECM]) cell cycle structure and regulation as key pathways in exercise response. This highlights the crucial role of mitochondria in determining exercise capacity and exercise response.
Therefore, the benefit of endurance exercise in PMD is highly dependent on the underlying mutation, although our results suggest an overall beneficial effect.