Because of the role of the mitochondria in metabolic and overall health, previous research has suggested that dysfunction in these organelles may have implications in conditions such as obesity and diabetes. Other conditions that mitochondrial dysfunction is involved in include age-related neurodegenerative conditions, such as Parkinson’s, Alzheimer’s, and Huntington’s disease. In fact, mitochondrial dysfunction may be at the root of the aging process, in general. Although also disputed, the so-called mitochondrial-free radical theory of aging is a popular one, and more than one study has suggested that boosting mitochondria’s health can prevent cells from aging. Previously, researchers thought that one molecular pathway that they called autophagy might offer precious clues to what keeps mitochondria healthy or makes them dysfunctional. Autophagy is a cellular survival pathway that recycles intracellular components to compensate for nutrient depletion and ensures the availabilty of buidling blocks. Recent evidence indicates anti-death protein Bcl-2 mediates exercise-induced autophagy and skeletal muscle adaptions to training during high-fat diet.
Therefore, it is key for the health of mitochondria, and previous studies have shown that exercise boosts autophagy, and the researchers believed that a high fat diet might impair the process. The latest research looked at this pathway in mice and examined the ways in which exercise and a high fat diet affect it, as well as how these changes affect mitochondrial health. The research was led by Dr. Sarah Ehrlicher, a PhD candidate in the College of Public Health and Human Sciences at Oregon State University in Corvallis. Ehrlicher and colleagues “stressed” the mitochondria of Bcl-2 transgenic mice by making the animals exercise on a treadmill. Genetic alterations impaired their exercise-induced autophagy pathway. The rodents were euthanized 36 hours after their last bout of exercise and 4 hours after their last meal, and the researchers examined the mitochondria in the rodents’ muscle cells. What the team found was that despite the genetic modification and the added stress of exercise, the mitochondrial function of the mice’s muscles remained intact. Then, the team fed the mice a high fat diet in addition to the exercise regimen to stress the mitochondria even more.
Again, the mice’s mitochondria showed signs of intact health and adaptation, even with the autophagy pathway blocked. This, explains the study’s lead author, suggests that the mitochondria have alternative ways to stimulate recycling and limit the damage. Dr. Matt Robinson, a senior researcher and corresponding author of the study, reported this way on the results: “When these animals were given a high fat diet, they got better at burning off those fats. If they were given just the exercise, they were able to make more mitochondria, which is good from an exercise perspective. And those adaptations seem to be very specific. The findings elucidate more about how mitochondria work and what keeps them healthy. The study helps lay some future groundwork for how we can optimize (muscle and mitochondrial) health to promote their health with diseases like obesity, diabetes, even some implications with aging — conditions that we know have compromised mitochondria. Exercise may be one such way of optimizing mitochondrial and metabolic health. Even without changes in weight, exercise has this amazing ability to improve metabolic health”.
Training increased protein synthesis rates and basal autophagy in the transgenic mice, while acute exercise activated autophagy mediated by proteins like BNIP3 (a Bcl-2 antagonist) and Parkin. Obese mice do not seem to have an obvious pathway dysfunction in their mitochondria, and the muscles just seem to respond and adapt well to new stress, whether that is exercise or a high fat diet. This suggests that similaryl humans with obesity may potentially benefit from exercise. In the future, the scientists hope to recruit human subjects to confirm their findings. The importance of these data were confirmed in another context, the one regarding satellite cells in human muscles. Satellite cells are responsible for muscle tissue regeneration and preservation, but to perform this function they have to remain quiescent in order to maintain tissue homeostasis. Throughout the subject’s life, they are activated by injury or by wear-and-tear due to exercise. Some then differentiate into tissue cells, while others self-renew, giving rise to new satellite cells so that the cycle can continue. But it’s not how originally scientists thought about them.
Findings at the University of São Paulo (USP) in Brazil, refuted the researchers’ initial hypothesis, which was that because aerobic exercise enhanced muscular oxidative capacity and satellite cells are anchored to the surface of skeletal muscle tissue (hence the name satellite), the oxidative capacity of satellite cells also ought to increase. Cellular respiration, the process by which chemical energy is released during the oxidation of organic molecules, occurs in mitochondria, organelles thought until recently to be responsible only for energy production. Scientists performed experiments using drugs to mimic the effect of reduced oxygen consumption on cells grown in the laboratory, and transplanting cells from exercised mice into sedentary mice. The reduction in oxygen consumption was indeed found to enhance satellite cell self-renewal. The rate of repair did not change in transplanted cells, but inflammation diminished, suggesting enhanced muscle recovery. The researchers now plan to investigate the effects of reduced mitochondrial oxygen consumption and the pathways involved in satellite cell self-renewal. The process is currently irreversible in many cases.
It may be possible to replicate this phenomenon in the future to treat age-related loss of muscle mass like genetic nuscuklar dystrophias and cancer-related muscle mass loss.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Abreu P et al. J Cachex Sarcop Muscle 2020; 11(6):1661.
Ehrlicher SE et al. FASEB J. 2020 Mar; 34(3):4602-4618.
Sanchez AM, Candau R, Bernardi H. Cells 2019 Jun 5; 8(6).
Dethlefsen MM et al. Physiol Rep. 2018; 6(13):e13731.
Dott. Gianfrancesco Cormaci
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