Stem cells tested on muscle ageing

“Scientists have created a ‘Mighty Mouse’ with muscles that stay powerful as it grows old,” the Daily Mail has reported. The newspaper said the ‘breakthrough’ paves the way for a “pill to give pensioners the strength of their youth, cutting the risks of falls and fractures in old age”.

The story comes from research on mice that found that transplanting donor muscle stem cells into injured leg muscles led to a 50% increase in muscle mass and a 170% increase in muscle size. The improvements were maintained though the lifetime of the mouse. The findings could have implications for treating the loss of muscle mass and strength that occurs in human ageing, say the researchers. It may also have implications for the treatment of muscle wasting diseases such as muscular dystrophy.

This laboratory study has provided intriguing findings but these are very preliminary as we are still a long way from developing a treatment to prevent loss of muscle mass in humans. Future research will first need to establish whether such transplants would be safe or effective in humans, which is likely to be a lengthy and challenging process.

Where did the story come from?

The study was carried out by researchers from the University of Colorado, Boulder and the University of Washington, Seattle in the US. It was partly funded by the US National Institutes for Health and the Muscular Dystrophy Association.

The study was published in the peer-reviewed journal, Science Translational Medicine.

The Daily Telegraph has provided good coverage of this story, without exaggerating the benefits findings to humans. BBC News importantly reported the view of an external expert on the difficulties of applying such research to humans. The Daily Mail coverage is perhaps overly optimistic in reporting that “the breakthrough paves the way for a pill to give pensioners the strength of their youth, cutting the risk of falls and fractures in old age”.

What kind of research was this?

This was a laboratory study using mice, in which the scientists tested the effects of injecting donor stem cells into injured skeletal muscle. Skeletal muscles are the muscles attached to bones. They are capable of continuous regeneration but this ability diminishes with age, resulting in loss of muscle mass and function. In humans this can result in reduce mobility, increased frailty, a high risk of injury and reduced quality of life.

How and why this happens is unclear, but loss of muscle mass is thought to be associated with changes in the capacity of skeletal muscle stem cells (also called satellite cells, which are located between muscle fibres and surrounding connective tissue) to repair and maintain skeletal muscle. Stem cells are special types of cells, with the ability to constantly renew themselves and differentiate into specialised cell types.

What did the research involve?

Researchers removed samples of leg muscle from three-month-old donor mice and isolated individual muscle fibres (myofibres) and their associated stem cells. They injected into the lower leg muscles of one leg of the host mice with a chemical (barium chloride) that would cause muscle injury. They then injected the same site with myofibres taken from the donor mice and cultured in a laboratory.

The uninjected leg of these mice acted as a control. As additional controls, donor cells were also injected into healthy (uninjured) leg muscle of other mice, and other mice just received the leg injury without a donor cell injection.

The donor mice had been genetically engineered to produce a green fluorescent protein in their cells, which mean the researchers could identify the donor cells in the injected host mice.

The researchers used various methods to measure the size and strength of the muscle, as well as the number of muscle fibres and muscle stem cells over a two-year period.

What were the basic results?

Muscles that had been injured and injected with donor cells displayed a 50% increase in muscle mass and a 170% increase in muscle size after two months. This was not seen in any of the three control models: the opposite legs of the treated mice, uninjured legs injected with the donor cells, or legs that were injured but were not injected with donor cells. 

The researchers found that the number of muscle fibres had increased by 38% 60 days after the transplant and by 25% almost two years after transplant. Most of these myofibres came from donor stem cells generating new muscle cells. Further experiments suggested that there was a persistent increase in the numbers of donor stem cells in the host mice.

The increase in muscle mass and size in the treated leg persisted for roughly two years, which is most of the lifespan of the mice. In addition, the ‘peak force’ (muscle strength) of the treated leg muscle at 27 months was about twice that of the untreated leg muscle.

How did the researchers interpret the results?

The researchers say that the transplants of skeletal muscle stem cells into injured leg muscle markedly alters the environment of young adult host muscle and leads to a ‘near-lifelong’ enhancement of muscle mass, as well as stem cell number. The researchers suggest that in the future, this finding could lead to the development of techniques to prevent or treat the muscle wasting and diminished function that occurs with ageing and with certain diseases.

Conclusion

This study has intriguing findings that the lead author described in The Daily Telegraph as being “fascinating, and something we need to understand”.

The differences between mice and humans mean that the results may not be indicative of what would be seen in humans. In particular:

• The smaller muscles in mice may respond in a different way from larger human muscles: although the muscle growth in mice took place over roughly two years (the average lifetime of the mice), it is not clear whether any potential effects would translate into lifetime improvements in longer-lived humans.
• The stem cell injections only prevented loss of muscle mass in muscles, which had been artificially injured, not in healthy muscle, indicating the need for injury before successful treatment. This may not be feasible in humans, and may not work on diseased muscle.
• The stem cells were transplanted into young, rather than aged, muscle. Therefore it is not clear whether similar effects would be seen if older mice were treated.
• Although the mice did not appear to mount an immune response to the transplant, there is also the question of whether transplants or injections of donor cells would be rejected by the human immune system.

This is early exploratory research that will no doubt lead to more research in order to understand what factors in the injured leg muscle have allowed the donor muscle stem cells to increase their regenerative ability and generate prolonged increases in muscle size and strength. Such research could eventually lead to treatments to counteract the effect on muscle or muscle wasting diseases, but is far from certain, and will take a considerable amount of time.