The regulation of muscle stem cell migration in ageing

The increase in the longevity of individuals in Western societies will present considerable challenges to the healthcare and economic systems of developed countries as they care for people whose body functions undergo age-related deterioration. Old age is associated with a progressive loss of skeletal muscle mass, a process called sarcopenia. Aged related muscle loss leads to lack of muscle strength, resulting in reduced posture and mobility, increased risk of falls, all of which contribute to a decrease in quality of life. Skeletal muscle contains stem cells that in the young are able to maintain mass. Aged muscle contains stem cells but these are not able to maintain mass.

We have recently shown that aged muscle stem cells move considerably slower than young stem cells and postulate that the ability to migrate is crucial in the repair process. Importantly we found that Nitric Oxide, a powerful cell signalling molecule, enabled old muscle cells stem to move at speeds of young cells.

In this investigation we aim to determine when mice develop deficits in migration speeds and how this correlates with changes in Nitric Oxide levels in muscle. We will then optimise the means of increasing Nitric Oxide levels in muscle and relate these to changes in muscle stem cell migration speeds. Finally we will use data generated from all previous section of this package to develop a regime that increases Nitric Oxide in aged muscle and determine whether it improves the muscle repair process.

We aim to show that increasing muscle stem cell migration using Nitric Oxide results in an enhanced rate of repair. Significantly, a number of drugs that increase Nitric Oxide levels have already been approved for use in humans. Therefore it is possible that results of our study could be rapidly translated into regimes to prevent age related muscle loss in humans.

Skeletal muscle contains a resident stem cell population called satellite cells that in the young have a remarkable capacity to generate precursors to facilitate muscle growth, homeostasis and repair. However satellite cells in aged muscle are not as potent and results in aged related muscle loss, a process called sarcopenia. Satellite cells are normally found in a quiescent state and become activated and then move to supplement existing muscle during tissue maintenance or to repair damaged tissue.

We have recently shown that aged satellite cells move at half the speed of young cells. Furthermore we have mathematically modelled movement and discovered that young cells migrate with diffusive (memoryless) characteristics whereas old cells move in a super diffusive manner typifying directionality. The speed and migration characteristic of old cells were converted to those of young cells by the action of Nitric Oxide.

We will use the results of our previous study as a platform to investigate in detail the relationship between Nitric Oxide and the migration of satellite cells. We will use time lapse video microscopy to determine how satellite cell migration speed change over time to identify when the speed deficit first manifests. Secondly we will use robust novel techniques to determine temporal changes in Nitric Oxide levels in skeletal muscle. Thirdly we will determine the efficacy three of regimes that increase Nitric Oxide signalling (either by direct exogenous provision of Nitric Oxide, increase in endogenous levels of nitric Oxide production or prolongation of intracellular signalling responses) on satellite cell migration speeds of aged satellite cells. Lastly we will use the optimal protocol promoting Nitric Oxide signalling to determine whether it improves whole muscle regeneration.

The long term impact of this research could be substantial. We suggest any treatment for muscle wasting may benefit a huge number of people since sarcopenia will affect many elderly people. Age-related muscle loss leads to lack of muscle strength, resulting in reduced posture and mobility, increased risk of falls, all of which contribute to a decrease in quality of life. In humans, sarcopenia first becomes evident at middle age. Large population studies have reported that over 20% of 60- to 70-year olds have sarcopenia and that the number reaches 50% in those over the age of 75 years. The number of people likely to be affected by sarcopenia will increase dramatically since Britain's population is ageing fast, with statisticians predicting that the proportion of people over the age of 60 may rise by 40% in the next 30 years. Half of these will suffer from sarcopenia.

The costs associated with caring for an ageing population are staggering and when expressed as a percent of Gross Domestic Product will increase from 19% in 2000 to 26% by 2050. Therefore any treatments developed as a consequence of basic research that will counter the effects of sarcopenia will have significant economic impact.

We believe that our work may stimulate the pharmaceutical industry to expand research into Nitric Oxide to develop drugs that are targeted to skeletal muscle.

Long term beneficiaries will extend to groups other than those directly affected by sarcopenia to include healthcare workers and the families and carers of the elderly.

The benefits of this work to the general public will be realised through the completion of not only this work but also on future studies based on the outcome of the proposed project. An optimistic estimate for the time required for the translation of this work into a safe and economic treatment would be in the order 10 years based on the development of novel approaches to regenerate skeletal muscle (e.g. through the use of exon skipping procedures).