On parallel paths
Calorie restriction and rapamycin protect muscles from aging in different ways
Yulia Panchenko, PCR.news
Aging inevitably leads to loss of muscle mass, which has a bad effect on the health of the whole body. To prevent this process and prolong active life, various methods are used; calorie restriction has proven itself well. But constant restrictions in food are an elusive task, so drugs that can mimic their effect are of great interest. It is believed that calorie restriction acts through the signaling pathways of mTORC1. The mTORC1 inhibitor, rapamycin, prolongs the life of yeast, flies, worms and mice. Long-term use of rapamycin also has a good effect on the skeletal muscles of mice. It remains unclear whether calorie restriction and rapamycin have the same mechanism of action, whether they can be combined. Scientists from Switzerland clarified this issue in mouse models.
The authors selected mice at the age of 15 or 20 months and gradually reduced their food intake to 65% of the initial level. At first, the mice lost weight, but then their weight normalized at a level 21-26% lower than the control. In order to adapt to lower calorie intake after fat loss, the mouse body absorbed energy better, while body temperature and energy consumption decreased.
Absolute grip strength decreased in both groups, but due to weight loss, relative grip strength was better in mice with limited calorie intake, although it also decreased over time. Calorie restriction had a positive effect on glucose levels. The metabolism of the mice has adapted to minimize energy expenditure. The authors suggest that these adaptations lead to an increase in life expectancy.
Calorie restriction also contributed to the transition from fast muscle fibers to slow ones. Slow muscle fibers are less susceptible to age-related changes. Therefore, in the experimental group, muscle mass decreased with age, but muscle functions remained.
Calorie restriction is thought to inhibit nutrient-induced mTORC1 activity. In this case, changes in gene transcription in muscle cells should be the same with diet and taking rapamycin. To test this hypothesis, the authors sequenced the mRNA of four muscle cells in mice aged 30 months. They found that the expression profiles were radically different in mice given rapamycin and in mice with restricted nutrition. In many clusters, rapamycin partially or completely reversed changes in gene expression associated with aging, while calorie restriction enhanced these changes. The levels of circulating proinflammatory cytokines were lower in both groups.
Next, the scientists limited calories in mice with constant activation of mTORC1 in muscles that develop sarcopenia quite quickly. These mice were characterized by the same changes in physiology and metabolism as wild-type mice. Calorie restriction did not inhibit mTORC1. The diet reduced the accumulation of p62 protein, but did not restore autophagy and did not reduce the signs of endoplasmic reticulum stress.
To understand whether the effects of calorie restriction and rapamycin overlap, the authors combined these two therapies. In such mice, body weight also decreased, and the relative strength of the grip improved. In animals on a calorie—limiting diet, glucose levels did not change when taking rapamycin, but the eating behavior changed - the mice ate more slowly. The positive effects of rapamycin on the muscles were also preserved. Thus, calorie restriction and taking the drug affected the processes occurring during aging, but their effects did not overlap and could be summed up.
Article by Ham et al. Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle is published in the journal Nature Communications.
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