Muscular degradation with age isn’t the result of a decline in the intrinsic regenerative ability of muscles, according to new research [1]. Instead, sarcopenia is likely due to changes in the muscle microenvironment that reduce repair and regeneration.
Declining muscles
Age-related muscle loss can begin as early as a person’s fourth decade, and sarcopenia can eventually lead to a cumulative loss of 30-50% of skeletal muscle mass. The complicated process involves a lot of interacting factors, including the gut microbiome and changes in the muscle microenvironment. Accumulating damage to muscle tissue doubtlessly plays a part, but it’s unclear why this damage doesn’t get repaired.
One suggested possibility has been that the mechanisms responsible for muscle repair might become exhausted with age; therefore, the quiescent muscle precursor cells that normally produce and regenerate muscle lose their ability to do so. However, it’s also possible that there is no change in the intrinsic competence of these cells and that muscle damage goes unrepaired because of changes in the muscle microenvironment.
To determine which of these possibilities is correct, a team of U.S. researchers developed and used a system to graft human muscles into mice. They collected muscle tissue from human cadavers that had undergone autopsies and transplanted it into mice. By using tissue from cadavers of people from different ages, they were able to evaluate the intrinsic regenerative ability of muscle cells at these ages.
Undaunted stem cells
The transplants were equally successful regardless of whether the tissue came from the body of a 36-year old or a 78-year old. Donor tissue from cadavers of various ages integrated into the mouse host and began producing muscle within three weeks and continued for at least six weeks. The researchers also carried out a transcriptomic analysis and detected the expression of human transcription factors involved in muscle differentiation.
These findings make it clear that precursor cells in elderly people retain the ability to generate muscle tissue. They do exactly that when placed in an appropriate environment, such as in healthy mice. The fact that the damage accumulates in elderly muscle tissue thus cannot be attributed to a decrease in the regenerative competence of these cells. The researchers argue that the most likely explanation is that changes in the muscle microenvironment somehow reduce regenerative competence.
The team also tested transplants of tissue after different post-mortem intervals to find out how long the cells retained their regenerative capacity. They found that the transplants were still successful after 11 days, the longest interval they tested. Not only were the transplants successful but there was no change in the success rate from shorter intervals. This suggests that the muscle results are highly resistant to the anoxic conditions of post-mortem tissues.
Age-related loss of muscle mass and strength is widely attributed to limitation in the capacity of muscle resident satellite cells to perform their myogenic function. This idea contains two notions that have not been comprehensively evaluated by experiment. First, it entails the idea that we damage and lose substantial amounts of muscle in the course of our normal daily activities. Second, it suggests that mechanisms of muscle repair are in some way exhausted, thus limiting muscle regeneration. A third potential option is that the aged environment becomes inimical to the conduct of muscle regeneration. In the present study, we used our established model of human muscle xenografting to test whether muscle samples taken from cadavers, of a range of ages, maintained their myogenic potential after being transplanted into immunodeficient mice. We find no measurable difference in regeneration across the range of ages investigated up to 78 years of age. Moreover, we report that satellite cells maintained their myogenic capacity even when muscles were grafted 11 days postmortem in our model. We conclude that the loss of muscle mass with increasing age is not attributable to any intrinsic loss of myogenicity and is most likely a reflection of progressive and detrimental changes in the muscle microenvironment such as to disfavor the myogenic function of these cells.
Conclusion
Figuring out how and why sarcopenia happens is obviously important to being able to address it, and this study brings us one step closer to that. The xenografting transplant approach, together with the demonstration that muscle tissue can be harvested from cadavers of different ages at varying times after death, will also likely prove useful tools in our efforts to understand and control sarcopenia.
