Caloric restriction and muscle regeneration

Can less be more? Apparently the answer is "yes" when the link between dietary intake and muscle regeneration is examined. Harvard Stem Cell Institute Executive Committee member Amy Wagers, PhD, and her lab team have long been studying how stem cells function throughout life to maintain, repair and regenerate cells and tissues. "We know," Wagers said, "that healing is much less effective in older individuals than younger individuals, but we don't know why that's so."

In looking for mechanisms that might be relevant to restoring regenerative potential in older skeletal muscle, Wagers, who was recently promoted to a full professorship in Harvard's Department of Stem Cell and Regenerative Biology, said, "I thought about mechanisms that had been studied for a long time evolutionarily as regulating life span and longevity, and particularly those that regulate the health of animals that live a long time. And it turns out," she noted, "that in a large number of organisms, reduced calorie intake — in the absence of malnutrition — has been shown to extend life span, particularly healthy lifespan."

Not only that, but animals that are kept on low calorie diets have a lower incidence of diabetes, cancer, and other chronic diseases and conditions. So Wagers and her team wondered whether the same kind of dietary intervention might affect stem cells in tissues. And what they found was pretty amazing

"Just a short intervention —12 weeks of a reduced calorie diet, which in a mouse is equivalent to a 40 percent reduction in the normal caloric intake, or for a person you can think of it as eating a meal and a half a day instead of three meals a day — has a positive effect," Wagers said. "In this context when these animals were challenged with muscle damage, they responded more vigorously and they repaired that damage more rapidly and more effectively. We could link this directly to changes in the stem cell population itself by isolating the cells and asking them to develop into muscle cells in culture." And they were more effective in doing that if they came from animals that had been on the reduced calorie diet, she explained.

"That led us to a next question," Wagers said. "Would we be able to use this as a mechanism for harnessing the regenerative potential of stem cells in a transplant setting? Transplantation is used quite extensively in the blood system to reconstitute blood cells after a bone marrow transplant, but it's not used widely in other tissue systems."

Wagers explained, "we had shown previously, with financial support from HSCI, that we were able to transplant muscle cells into mice with muscular dystrophy, and they were able to graft, reconstitute the muscle, and provide a therapeutic benefit in that the muscles contracted with greater force." But it was difficult to get the cells in sufficient numbers to transplant.

So then the Wagers team asked whether caloric restriction also would increase the transplant potential of stem cells, and "what we found was that we got about twice as many fibers out of the transplanted cells. That says we can use this relatively simple dietary intervention as a way of getting a ‘more for less' transplant strategy."