The effect of calorie restriction on mouse haematopoetic and skeletal muscle stem cells.
Lead Research Organisation:
University College London
Department Name: Institute of Child Health
Abstract
Ageing leads to a reduced capacity to maintain tissues, or to repair them after injury, most likely due to age-related changes in stem or precursor cells. Skeletal, or voluntary, muscles have stem cells called satellite cells that contribute to the growth, repair and regeneration of muscle. The size of muscle fibres is controlled by satellite cells and by hormonal and biochemical signals, that balance the rates of protein synthesis and degradation. But beyond middle age, muscle mass is not maintained leading to the loss of skeletal muscle mass and strength associated with ageing, termed sarcopenia. Because of increasing longevity in Western populations, sarcopenia is becoming a serious health problem, as it leads to frailty, poor balance, slow movement, falls, and fractures. Blood cells are derived from haematopoietic stem cells, multipotent stem cells that give rise to all blood cells of the myeloid and lymphoid lineages. Alterations in haematopoietic stem cells with age lead to increased susceptibility to anaemia, infectious diseases and cancers.
Calorie restriction is a diet that restricts the intake of calories, without leading to malnutrition, which has been shown to slow the ageing process and improve health in some animals. It appears to slow down some of the defects in the haematopoietic system and skeletal muscle that occur as a result of age, but it is not known if it prevents or retards sarcopenia, or improves the function of haematopoietic stem cells in old age. We will therefore investigate whether calorie restriction does indeed help to maintain effective haematopoietic and skeletal muscle systems in ageing mice. We will do this by determining if there is a prevention of, or reduction in, defects that are known to occur in skeletal muscle and the haematopoietic system with increasing age, focussing in particular on the function of the stem cells that maintain both these vital body systems.
Calorie restriction is a diet that restricts the intake of calories, without leading to malnutrition, which has been shown to slow the ageing process and improve health in some animals. It appears to slow down some of the defects in the haematopoietic system and skeletal muscle that occur as a result of age, but it is not known if it prevents or retards sarcopenia, or improves the function of haematopoietic stem cells in old age. We will therefore investigate whether calorie restriction does indeed help to maintain effective haematopoietic and skeletal muscle systems in ageing mice. We will do this by determining if there is a prevention of, or reduction in, defects that are known to occur in skeletal muscle and the haematopoietic system with increasing age, focussing in particular on the function of the stem cells that maintain both these vital body systems.
Technical Summary
Defects in stem cells are implicated in the age-related decline in the function of many organ systems. Skeletal muscle repair, maintenance and regeneration are mediated by satellite cells, muscle-specific stem/precursor cells. However, there are other stem cells present within skeletal muscle that can contribute to regeneration after grafting into host mice, but the relevance of these to routine muscle repair is not known. Despite the presence of stem cells in adult muscles, skeletal muscle mass and its ability to regenerate following injury are reduced with increasing age, but it is unclear whether this is due to a defect in muscle stem cells, the local or systemic environment, or a combination of these.
Age-related changes in the haematopoietic system lead to increased incidence of leukemias, a decline in adaptive immunity, and greater tendency to anaemia. Haematopoietic stem cells (HSC) from old mice have altered homing and mobilization, reduced repopulating ability, increased capacity to give rise to myeloid and reduced capacity to give lymphoid progenitors.
Calorie restriction has been shown to increase lifespan and reduce or delay the onset of many age-related defects. But there appears to be a mouse strain-specific difference in the response to calorie restriction, as it increases lifespan in C57BL/6, but not DBA/2, mice. However, the effect of calorie restriction on skeletal muscle stem cells and their regenerative ability is not known. As there is a differential response to calorific restriction between C57BL/6 and DBA/2 mice, we propose to investigate the effect of calorie restriction in both strains of mice on skeletal muscle histopathology and on the number and function of satellite and other stem cells present within skeletal muscle. Simultaneously, we will investigate the effects of calorie restriction on HSC frequency and functional output in these two contrasting mouse models.
Age-related changes in the haematopoietic system lead to increased incidence of leukemias, a decline in adaptive immunity, and greater tendency to anaemia. Haematopoietic stem cells (HSC) from old mice have altered homing and mobilization, reduced repopulating ability, increased capacity to give rise to myeloid and reduced capacity to give lymphoid progenitors.
Calorie restriction has been shown to increase lifespan and reduce or delay the onset of many age-related defects. But there appears to be a mouse strain-specific difference in the response to calorie restriction, as it increases lifespan in C57BL/6, but not DBA/2, mice. However, the effect of calorie restriction on skeletal muscle stem cells and their regenerative ability is not known. As there is a differential response to calorific restriction between C57BL/6 and DBA/2 mice, we propose to investigate the effect of calorie restriction in both strains of mice on skeletal muscle histopathology and on the number and function of satellite and other stem cells present within skeletal muscle. Simultaneously, we will investigate the effects of calorie restriction on HSC frequency and functional output in these two contrasting mouse models.
Planned Impact
1. Academic impact.
The proposed project is relevant to the BBSRC topical issue - research on ageing - and also to the BBSRC strategic plan 2010-2015 Strategic research priority 3: Basic bioscience underpinning health: Generate new knowledge of the biological mechanisms of ageing, and the maintenance of health. The project is also pertinent to the next phase of the RCUK programme on Lifelong Health and Wellbeing, ensuring that outcomes are translated to improve quality of life for the ageing population.
The loss of muscle mass and strength with age, termed sarcopenia, is a fundamental element of frailty; the consequences of sarcopenia are therefore of tremendous socio-economical importance in an increasingly elderly population. The loss of muscle mass and function with age represents a major cause of impairment in day-to-day activity and are a major cause of falls that frequently lead to fractures and hospitalization.
2. Societal impact.
Our project is basic research, so the outcomes will not have an immediate direct impact on either human health or health policy, but will provide invaluable information on the role of haematopoetic and muscle stem cells in maintaining organs and how the function of muscle and haematopoetic stem cells may be improved in ageing individuals.
3. Public engagement.
We will communicate with and engage the public as appropriate on the involvement of skeletal muscle stem cells in sarcopenia and our research efforts to find treatments to reduce or decelerate loss of skeletal muscle with age.
4. Economic impact.
Outcomes from this project will have no immediate impact on the UK economy, but we will have trained two postdoctoral research assistants, who will then be able to develop their own research interests, leading to future expanse in this key area. However, if they do not continue in research, they will have received training in analytical skills that will enhance their employment prospects.
We will pursue potential patents and spin-offs that result from findings from our research project.
The proposed project is relevant to the BBSRC topical issue - research on ageing - and also to the BBSRC strategic plan 2010-2015 Strategic research priority 3: Basic bioscience underpinning health: Generate new knowledge of the biological mechanisms of ageing, and the maintenance of health. The project is also pertinent to the next phase of the RCUK programme on Lifelong Health and Wellbeing, ensuring that outcomes are translated to improve quality of life for the ageing population.
The loss of muscle mass and strength with age, termed sarcopenia, is a fundamental element of frailty; the consequences of sarcopenia are therefore of tremendous socio-economical importance in an increasingly elderly population. The loss of muscle mass and function with age represents a major cause of impairment in day-to-day activity and are a major cause of falls that frequently lead to fractures and hospitalization.
2. Societal impact.
Our project is basic research, so the outcomes will not have an immediate direct impact on either human health or health policy, but will provide invaluable information on the role of haematopoetic and muscle stem cells in maintaining organs and how the function of muscle and haematopoetic stem cells may be improved in ageing individuals.
3. Public engagement.
We will communicate with and engage the public as appropriate on the involvement of skeletal muscle stem cells in sarcopenia and our research efforts to find treatments to reduce or decelerate loss of skeletal muscle with age.
4. Economic impact.
Outcomes from this project will have no immediate impact on the UK economy, but we will have trained two postdoctoral research assistants, who will then be able to develop their own research interests, leading to future expanse in this key area. However, if they do not continue in research, they will have received training in analytical skills that will enhance their employment prospects.
We will pursue potential patents and spin-offs that result from findings from our research project.
Organisations
Publications
Whitmore C
(2014)
What do mouse models of muscular dystrophy tell us about the DAPC and its components?
in International journal of experimental pathology
White MJ
(2016)
Calorie Restriction Attenuates Terminal Differentiation of Immune Cells.
in Frontiers in immunology
Boldrin L
(2017)
The effect of calorie restriction on mouse skeletal muscle is sex, strain and time-dependent.
in Scientific reports
| Description | It is known that calorie restriction (a diet low in calories without under-nutrition) increases the lifespan of one strain of mice, (C57Bl/6), but not in the shorter-lived DBA/2 mouse strain. We therefore investigated whether calorie restriction improves the function of the immune system and skeletal muscle in both strains of mice. We compared T cells and natural killer (NK) cells from calorie restricted and control (fed ad libitum) C57BL/6 and DBA/2 mice. We found that calorie restriction preserves a naïve T cell phenotype and an immature NK cell phenotype, that is normally lost as the mice age. Although calorie restriction attenuates these age-associated changes, the effects of calorie restriction on lymphocyte maturation were more marked in C57BL/6 than in DBA/2J mice, indicating that delayed lymphocyte maturation correlates with extended lifespan. These findings have implications for understanding the interaction between nutritional status, immunity, and healthy lifespan in aging populations. Loss of skeletal muscle mass and function occurs with increasing age. There is some evidence that calorie restriction reduces or delays many of the age-related defects that occur in rodent skeletal muscle. We therefore investigated the effect of short (2.5 month) and longer term (8.5 and 18.5 months) calorie restriction on skeletal muscle in male and female C57Bl/6 and DBA/2 mice. We found that short-term calorie restriction increased the number of skeletal muscle stem (satellite) cells and that satellite cells derived from calorie restricted mice divided more slowly when they were placed in culture. Short-term calorie restriction increased the amount of skeletal muscle connective tissue, but resulted in a delayed regenerative response to muscle injury. The percentage of connective tissue cells and immune cells (macrophages and hematopoietic stem cells) within the skeletal muscle was reduced by calorie restriction. But overall, these changes were neither consistent over time, nor between strain and sex. The fact that changes in skeletal muscle cells induced by calorie do not persist with time and the dissimilarities between the two mouse strains, combined with sex differences, urge caution in applying calorie restriction to improve skeletal muscle function across the lifespan in humans. |
| Exploitation Route | Investigating why calorie restriction is beneficial to immune cells but does not have such a clear effect on skeletal muscle in the same mouse will be of interest to the scientific community. Finding genetic modifiers that modulate the beneficial effect of calorie restriction (or pharmacological agents that mimic calorie restriction) will lead to personalised medicine approaches to improve stem cell function during aging. |
| Sectors | Healthcare |