Two studies published in Nature Metabolism have found that chaperone-mediated autophagy (CMA), a cellular recycling process, is crucial for maintaining muscle health. The research, which used animal models and human muscle samples, was led in part by Ana Maria Cuervo, M.D., Ph.D., of Albert Einstein College of Medicine.
“Sarcopenia or muscle wasting often accompanies aging, affecting half of all people over age 80 and significantly raising their risk for falls, injuries, and hospitalizations,” said Dr. Cuervo. “One of our interesting findings is that simple lifestyle interventions, such as exercise and fasting, can boost CMA activity and help prevent age-related muscle wasting.”
CMA enables cells to remove damaged or unnecessary proteins and reuse their components to make new proteins. Previous work by Dr. Cuervo’s team showed that reduced CMA activity leads to the buildup of cellular waste in nerves and other cells, contributing to diseases like Alzheimer’s.
In these new studies, researchers developed two mouse models lacking CMA activity in either muscle fibers or muscle stem cells from a young age. Mice without CMA in their muscle fibers accumulated damaged proteins that impaired contraction and caused weakness. When CMA was disabled in muscle stem cells, the ability to produce new muscle cells after injury dropped sharply. These results mirrored changes seen in human age-related muscle loss.
The researchers also found that increasing CMA activity—either genetically or with drugs—in older mice improved their muscles’ function and regenerative abilities.
Additionally, the studies revealed that poor nutrition (such as high-fat diets) and aging both reduce CMA activity in skeletal muscles. In contrast, exercise and fasting were shown for the first time to enhance CMA activity in mice.
Dr. Cuervo explained: “As we age, a decline in CMA activity is noticeable in multiple organs including muscle. We found this in the muscle from both our mouse models and in healthy, elderly people that we examined as part of this study—even before clear evidence that muscle function has deteriorated. We also found that the muscles of elderly patients with sarcopenia had markedly reduced CMA activity.” She added: “Our findings identify CMA as a vital guardian of muscle integrity and a promising target for preventing or treating sarcopenia in aging populations.”
The first paper is titled “Age-related decline of chaperone-mediated autophagy in skeletal muscle leads to progressive myopathy” with Dr. Cuervo as senior author alongside Olaya Santiago-Fernandez leading the project. The second paper is titled “Chaperone-mediated autophagy sustains muscle stem cell regenerative functions but declines with age,” co-authored by Dr. Cuervo and Pura Muñoz-Cánoves from Altos Labs San Diego Institute of Science.
