Benefits of exercise may vary greatly in primary mitochondrial disease
While the benefits of exercise may outweigh the risks, genetic status
should be considered when recommending it as therapy

Date:
May 4, 2022
Source:
Children's Hospital of Philadelphia
Summary:
Researchers demonstrated that the benefits of endurance exercise
can vary based on the type of mutation involved in mitochondrial
disease, and while the benefits of exercise tend to outweigh the
risks, the mitochondrial genetic status of patients should be
taken into consideration when recommending exercise as therapy.



FULL STORY ========================================================================== Mitochondria serve as the main source of energy production in our cells,
and endurance exercise is generally known to improve the function of mitochondria.

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) demonstrated that the benefits of endurance exercise can vary based
on the type of mutation involved in mitochondrial disease, and while
the benefits of exercise outweigh the risks, the mitochondrial genetic
status of patients should be taken into consideration 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 every 4,200
people. These disorders can be caused by hundreds of different mutations
in the nuclear DNA (DNA within our cells) or mitochondrial DNA (mtDNA, or
the DNA within the mitochondria within 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 diorders.

However, these recommendations were based on healthy people without
primary mitochondrial disease. Therefore, researchers wanted to determine effectiveness for these patients and whether they are actually benefitting
from endurance exercise.

"There was not a concensus among clinicians who see patients with
mitochondrial disease whether endurance exercise truly offers benefits,"
said Patrick Schaefer, PhD, a postdoctoral fellow at the Center for Mitochondrial and Epigenomic Medicine at 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,
there is a chance that exercise may put some patients at risk." Because
of the heterogeneity of primary mitochondrial disease among patients, the researchers used animal models to study five mutations responsible for the disease. The goal of the study was to determine the relationship between mitochondrial mutations, endurance exercise response, and the underlying molecular pathways in these models with distinct 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, 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 exercise response
and identified oxidative phosphorylation, amino acid metabolism, and
cell cycle regulation as key pathways in exercise response, suggesting
how the model might be adapted to study exercise responses in humans
with primary mitochondrial disease.

Despite mixed responses of 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 should be taken into account when recommending therapeutic exercises. Additionally, the study
could help researchers identify biomarkers and pathways to help predict
the mitochondrial response to exercise both in 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 senior study author Douglas C. Wallace,
PhD, director of the Center for Mitochondrial and Epigenomic Medicine
at CHOP and the Michael and Charles Barnett Endowed Chair in Pediatric Mitochondrial Medicine and Metabolic Diseases. "This is of broad relevance
to individuals ranging from athletes to patients with mitochondrial
disease, and everyone in between." This study was supported by the German Research Foundation through grant SCHA 2182/1-1, the National Institutes
of Health grants NS021328, MH108592, and OD010944, and U.S. Department
of Defense grants W81XWH16-1-0401 and W81XWH-21- 1-0128. Schematics were created with BioRender.com.


========================================================================== Story Source: Materials provided by
Children's_Hospital_of_Philadelphia. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Patrick M. Schaefer, Komal Rathi, Arrienne Butic, Wendy Tan,
Katherine
Mitchell, Douglas C. Wallace. Mitochondrial mutations alter
endurance exercise response and determinants in mice. Proceedings
of the National Academy of Sciences, 2022; 119 (18) DOI:
10.1073/pnas.2200549119 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/05/220504110430.htm

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