Plant-Based Substance Reduces Age-Related Muscle Weakness in Mice, Study Reveals

Highlights:

• Administration of farnesol prevented muscle weakness and metabolic misregulation in aged mice.
• Farnesol treatment also enhanced muscle “stem cell” growth and regenerative capacity.
• These results suggest that farnesol might prevent muscle weakness related to aging or disease conditions.

Giving old mice a natural compound called farnesol, found in Japanese honeysuckle and other plants, made their muscles stronger and their metabolisms work better. Also, muscle injuries healed faster after treatment with farnesol because muscle stem cells worked better. The current study by the Samsung Advanced Institute of Technology, Samsung Biomedical Research, Sungkyunkwan University School of Medicine, and John Hopkins University suggests that farnesol treatment can restore muscle function in older mice. The work was published in Science Translational Medicine.

At The Heart of Muscle Loss

Skeletal muscle atrophy, also called sarcopenia, is the loss of strength and mass that comes with getting older. This makes people more likely to get hurt and less able to heal from injuries. When a muscle’s ability to repair itself gets worse, the number of satellite cells, muscle stem cells, and cells that respond to activation cues gets lower. This can lead to less cell growth or cellular senescence — a critical state where cells no longer grow or divide. So far, exercise has proven to be the best treatment for both preventing and treating sarcopenia. When you work out to build endurance, you increase the number of muscle fibers full of mitochondria. Muscle fibers with more mitochondria are better at using energy and metabolizing it. 

Even though the exact way exercise stops sarcopenia is still unclear, it seems that a molecule called peroxisome proliferator-activated receptor-coactivator-1-α (PGC-1α) is a key player. This molecule controls the genes that affect the growth of blood vessels, how muscles use energy, and the synthesis of mitochondria. Also, multiple studies have reported the protective effects of elevated PGC-1α against sarcopenia and aging-related metabolic diseases, such as type II diabetes and hepatic steatosis. Studies have shown that mice without PGC-1α have a slower muscle metabolism and less ability to exercise, while mice with increased levels of active PGC-1α in muscles are less likely to lose muscle as they age, which is good for the health of the whole body. Also, increased PGC-1α activity in muscles protects muscles from damage by enhancing muscle regeneration. So, increasing the amount of PGC-1 in skeletal muscle could be a way to prevent and treat sarcopenia. 

Farnesol Enhances Aged Muscle Function

In this study, Bae and colleagues looked for compounds that increased the amount of PGC-1 in muscles. The team found that farnesol increased the activity of genes that are important for muscle and mitochondrial health in both mouse and human cells. To see what effect farnesol has on muscle in living animals, 5-month-old adult mice were fed food with farnesol added to it for five weeks. Bae and his colleagues found that the levels of PGC-1 and genes important for muscle health were much higher in the leg muscles of mice fed farnesol. Treatment with farnesol made muscle fibers bigger and boosted their metabolism.

To see what effect farnesol has on muscle function in old mice, 26-month-old mice were given farnesol by mouth for one month, and their muscle strength was measured. Aged mice given farnesol had more muscular calf muscles (soleus muscles) and showed improved strength across many muscle groups compared to aged mice fed chow. In line with the fact that PGC-1 helps keep muscles from getting weak, giving farnesol to older mice increased their metabolism and energy use in their muscles and whole bodies. This beneficial effect of farnesol was specifically linked to better metabolic properties, like better glucose response, body fat mass ratio, fat buildup in the liver and white adipocytes, and blood cholesterol levels. Also, farnesol treatment increased the capillary density in the muscles of aged mice, suggesting that blood vessel formation might be contributing to the beneficial effect of farnesol on muscle function. 

Farnesol Enhances Aged Muscle Regeneration

Next, Bae and the team looked at how farnesol affects muscle scarring (fibrosis), which is linked to muscle weakness and less ability to heal in older muscles. They found that old mice that were fed farnesol had less fibrosis in their muscles than old mice that were fed chow. When comparing farnesol-fed mice to chow-fed mice, the activity of fibrosis-related genes was always lower in the muscles of farnesol-fed mice. Farnesol made it easier for muscles to heal themselves by increasing the number and health of muscle stem cells, making it easier for mitochondria to make new cells, and reversing the changes in muscle and mitochondrial gene activity that come with getting older.

In a model of muscle injury, Bae and his colleagues found that 21 days after the injury, mice given farnesol had myofibers in the tibia muscles that grew more than in untreated mice. When compared to groups that were given a vehicle, groups that were given farnesol had less fibrosis and more muscle, with about a 30% increase in the number of new cells that grew in damaged areas and better muscle stem cell maintenance and growth.

Just Another Exercise Mimetic?

Several exercise mimetics activating the upstream of PGC-1α, such as AICAR and GW1516, have shown the potential for clinical use to treat sarcopenia or conditions related to physical immobility. However, these compounds have potential side effects, such as increased risks of heart defects and cancer. Encouragingly, there was no cardiac hypertrophy observed in farnesol-treated mice.

In humans, the loss of muscle strength occurs faster than that of muscle mass during aging, and impaired muscle strength seems to be more closely associated with mortality during aging. Similar to the effect of AICAR on muscle strength in sedentary mice, farnesol improved muscle function and metabolism in sedentary mice. As with other exercise mimetics, the combination of farnesol treatment and exercise may be an effective strategy to boost its beneficial effect.