Researchers show that aging muscle satellite cells undergo an irreversible transition from quiescence to senescence leading to impaired muscle fiber regeneration observed in elderly patients. The molecule responsible is tumor-supressing protein p16INK4a.
One of muscles’s greatest strengths is its response to injury. Muscle tissue uses many injuries as an opportunity to make itself stronger. Many athletes, for example, take advantage of this phenomenon when training. Repeated injury to the muscle fibers during training causes the fibers to regrow and repair themselves so that the muscle as a whole is strengthened. Satellite cells attached to the muscle fibers play a fundamental role in this process because they act as stem cells producing new muscle fibers when the muscle is damaged.
Satellite cells are normally in a reversible quiescent state, meaning they have exited the cell cycle into G0 phase where they are not actively dividing. Damage to the muscle fiber causes to the satellite cell to reenter the cell cycle and produce new muscle progenitors cells, which eventually generate mature muscle fibers. The satellite cells continue to produce new muscle fibers until the muscle is repaired. However, when this system fails it leads to muscle deterioration (or atrophy). Severe muscle deterioration to the point of dysfunction is called sarcopenia and commonly seen in people of old age or with the disease progeria. The figure below illustrates the process of muscle generation in healthy patients and patients with sarcopenia.
The muscle fails to regenerate after the satellite cells enter a senescent state. In a senescent state the satellite cell is incapable of reentering the cell cycle and spawning new stem cells. A new study published last month in Nature has found a molecule that may be responsible for driving the satellite cell into a senescent state (Geriatric muscle stem cells switch reversible quiescence into senescence, 2014. Pedro Sousa-Victor, et al.).
Increased expression of tumor-supressor molecule p16INK4a was found in the senescent satellite cells of both progeria and geriatric mice models. To further demonstrate its ability to cause sarcopenia, researchers silenced the expression of p16INK4a using short hairpin RNA. Nearly 30% of geriatric satellite cells in culture were activated following p16INK4a silencing compared to less than 15% of cultured geriatric satellite cells without p16INK4a silencing. When young cultured satellite cells were treated with p16INK4a their regeneration activity dramatically decreased. These findings were confirmed in humans with muscle biopsies of geriatric patients with sarcopenia and young adults. The elderly patient biopsies had significantly higher levels of p16INK4a expression compared to young adults of average age 25. It appears that the increased p16INK4a expression drives the satellite cells into the senescent state by hindering the phosphorylation of restinoblastoma. The inactivation of restinoblastoma irreversibly arrests the satellite cell in the G0 phase of the cell cycle.
This study poses many further questions. Would it be possible to use p16INK4a silencing as a therapy for progeria and geriatric muscle sarcopenia? The experiments done in cultured mice satellite cells are encouraging, but whether it would carry over to humans remains to be seen. Furthermore, what causes p16INK4a expression to increase? The authors suggest that one possibility is simply the same genomic decay that is responsible for most cancers. Could reduced physical activity play a role? If so, this would be one more biological phenomenon that follows the “use it or lose it” principle.