Ketogenic diet promotes muscle stem cell resilience but delays injury recovery in mice

Fasting sends muscle stem cells into a deep state of rest that slows muscle recovery but also makes them more resistant to stress, according to a Stanford Medicine study of lab mice.

The protective effect can also be achieved by feeding the mice high-fat, low-carb foods — also known as a ketogenic diet — that mimic how the body responds to fasting, or by giving the animals ketone bodies, the byproducts that occur when the body uses fat. as an energy source.

The study explores how the body responds in times of hardship and abundance and provides clues about the effect of aging on the ability to regenerate and repair damaged tissue. Although the study focused on muscle stem cells, the researchers believe the findings apply to other types of tissue throughout the body.

As we age, we experience a slower and less complete healing of our tissues. We wanted to understand what controls that regenerative ability and how fasting affects this process. We found that fasting induces resilience in muscle stem cells so that they survive during deprivation and are available to repair muscle when nutrients are available again.”

Thomas Rando, MD, PhD, professor of neurology and neurological sciences

Rando, who recently accepted a position as director of the Broad Stem Cell Research Center at UCLA, is the senior author of the study, which was published online June 7 in cell metabolism† Lecturer Daniel Benjamin, PhD, and PhD student Pieter Both are the lead authors of the study.

Calorie restriction

It is well documented that long-term calorie restriction extends lifespan and promotes the overall health of laboratory animals, but it is difficult for humans to follow a very low-calorie diet for months or years. Intermittent fasting has been researched as another way to obtain the health benefits of calorie restriction, but the effects of intermittent fasting on the body and its ability to regenerate damaged or aging tissue have not been well studied.

Fasting or, alternatively, eating a high-fat, low-carb ketogenic diet — a popular weight-loss technique — puts the body into a state called ketosis, in which fat is the primary source of energy. Ketone bodies are the byproducts of fat metabolism.

The researchers found that mice that had fasted between 1 and 2.5 days were less able than non-fasting animals to regenerate new muscles in their hind legs in response to injury. This reduced regenerative ability persisted for up to three days after the mice started eating again and returned to normal body weight; it returned to normal within a week of the end of the fast.

Further research showed that muscle stem cells from fasting animals were smaller and dividing more slowly than those from non-fasting animals. But they were also more resilient: They survived better when grown on a lab scale under challenging conditions, including nutrient deprivation, exposure to cell-damaging chemicals and radiation. They also survived transplantation in animals better than those of non-fasting animals.

“Usually, most lab-grown muscle stem cells die when transplanted,” Rando said. “But these cells are in a deep resting state we call ketone-induced deep rest, which allows them to withstand many types of stress.”

Muscle stem cells isolated from non-fasting animals and then treated with a ketone body called beta-hydroxybutyrate (BHB), showed similar resilience to that of fasting animals, the researchers found. In addition, muscle stem cells isolated from mice fed a ketogenic diet, or a normal diet combined with injections of ketone bodies, showed the same characteristics of the deeply dormant stem cells from fasting animals.

Finally, the researchers isolated muscle stem cells from old mice that had been treated with ketone bodies for a week. Previous research in Rando’s lab showed that these aged muscle stem cells grew worse in the lab than muscle stem cells from younger animals. But treatment with the ketone bodies allowed the old muscle stem cells to survive just as well as their younger counterparts.

Potential Applications

While more research needs to be done, the results are intriguing, the researchers said.

“Cells have evolved to exist in times of abundance and in times of hardship,” Rando said. “They needed to be able to survive when food was not readily available. Ketone bodies form when the body uses fat for energy, but they also push stem cells into a resting state that protects them during deprivation. In this state, they are protected from environmental stress, but they are also less able to regenerate damaged tissue.”

Balancing these results could one day help reverse normal aging and improve stem cell function throughout the body, the researchers speculated.

“It would be beneficial if the effects of fasting on stem cells could be achieved through ketone bodies, replacing the need to fast or follow a ketogenic diet,” Rando said. “Maybe it’s possible to eat normally and still get this increased resilience.”

The research was supported by the National Institutes of Health (grants T32GM119995-1A1, PO1AG036695, R37AG023806 and RO1AR073248), the Buck Institute for Research on Aging and the Department of Veterans Affairs.

Researchers at UC Berkeley; the Veterans Affairs Palo Alto Health Care System and the Mondor Institute for Biomedical Research in France are co-authors of the study.


Reference magazine:

Benjamin, D.I., et al. (2022) Fasting induces a highly resilient deep resting state in muscle stem cells via ketone body signalling. Cell metabolism.

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