The human body is about 40% skeletal muscle. Apart from the roles it plays in body support and structure, locomotion and cardio-respiratory functions, muscle is the greatest contributor to whole body metabolism of glucose, fats and proteins. Excess levels of these are implicated in diverse human diseases. Thus defects in muscle metabolism underlie or exacerbate diseases like diabetes, cancer and rheumatoid arthritis. Research in my lab focuses on molecular mechanisms regulating skeletal muscle protein metabolism and growth, and how these are modulated by interactions between physical activity and nutrition in health and disease states. I study insulin and nutrient signaling and their effects on mRNA translation initiation in skeletal muscle, and the ubiquitin proteolytic system.
It is one of the paradoxes of life that sometimes things that do good can, under some circumstances, have a dark side. Amino acids are critical regulators of muscle mass and metabolism. However they may also negatively affect insulin actions in our bodies. This condition (insulin resistance) is at the root of diseases like type 2 diabetes and cardiovascular disease. Therefore another focus of my research is the examination of mechanisms of insulin resistance in muscle and how these are modified by nutrition and physical activity.
My primary focus is on the breakdown (assembly and disassembly) of striated muscle organelles and the role of calcium activated proteases, in particular calpain (CAPN1-2), during the control of these processes in health and disease. In addition to the activation and regulation of CAPN1-2, studies aimed identifying the factors contributing to the targeting of selected muscle proteins marked for breakdown are underway. Finally, the Paediatric Exercise Physiology Laboratory is focused on the study of improvement of children’s muscle health and fitness through physical activity.
Our smallest blood vessels named “capillaries” are responsible for delivering oxygen and nutrients to our muscles. For this reason, they are extremely important for the good function of our skeletal muscles. Research in the Birot lab focuses on understanding how these capillaries respond to healthy and pathological conditions. How does exercise training increase the number of capillaries, thus contributing to improve muscle function? Through which mechanisms can diabetes lead to a loss of these vessels? How physical exercise can counteract the effect of diabetes on capillaries? These are a few of the questions we aim to answer! Our translational approach from benchtop to patients combines start-of-the-art laboratory techniques, cell culture, and analysis of human muscle biopsies in collaboration with university hospitals in Canada and abroad.
Dr. Ceddia's research program is designed to develop a greater understanding of the basic fundamental physiological and molecular mechanisms involved in the regulation of substrate partitioning and energy balance at the cell, tissue, and whole-body levels. It includes in vivo and in vitro experiments to elucidate the contribution of major organs that integrate lean body mass (LBM) to whole-body energy metabolism. It mainly focuses on understanding the energy-sparing and energy-dissipating mechanisms that are activated under conditions of altered food intake (energy deficit and surplus) and energy expenditure (chronic endurance exercise). This is important because the ability to store and conserve energy is essential for survival and reproductive capacity, and it is affected by diet, exercise, and hormonal secretions. The main objectives are:
- To determine the time-course effects of food restriction and energy surplus, as well as of exercise-mediated increased energy expenditure and reduced fat mass on 24-hour whole-body energy balance
- To assess acute and chronic adaptations in metabolic partitioning in skeletal muscle, liver, kidney, and heart to food restriction and energy surplus, as well as to exercise-mediated increased energy expenditure
- to determine the effects of acute and chronic energy restriction and surplus and exercise-mediated increased energy expenditure on the hypothalamus-pituitary-thyroid (HPT) axis.
In order to maintain normal body function, the body is continually adapting to external stressors, which activates numerous hormonal pathways and alters the body’s physiology. The stress response is designed to be short term, but when maintained over long periods the body undergoes chronic deleterious adaptations stress exposure. Glucocorticoids (GCs) are a major component of the stress response and chronic elevations of GCs are associated with many body responses including overt weight gain, which is accompanied by the development of insulin-resistance, type II diabetes, enhanced production of inflammatory proteins, the release of hormones from adipose tissue and loss of skeletal muscle mass (sarcopenia), brought about by activation of numerous intracellular signalling pathways. In addition to loss of muscle mass, chronic GC exposure also leads to impaired skeletal muscle damage repair. The latter two effects of GC elevation may be a result of impairments in the ability of skeletal muscle cells to repair and regenerate themselves. This may be a result of a growth inhibitory environment created by the presence of GCs, inflammatory cytokines and adipokines that prevent muscle regeneration. This proposal is designed to evaluate the effects of GCs on skeletal muscle cell cycle regulation and identify some of the pathways that mediate these effects. We will evaluate whether GCs and adipokines affect muscle cell proliferation and differentiation and evaluate whether adipocyte alterations, inflammatory cytokine alterations and circulating hormone changes induced by chronic GC elevation affect the ability of skeletal muscle cells to proliferate and differentiate. This research will be the first to evaluate the interactions between GCs, cytokines and adipokines on skeletal muscle cell cycle regulation and will provide valuable insight into the stress- induced deleterious effects on skeletal muscle maintenance and repair properties elicited by chronic GC exposure.
A sedentary lifestyle coupled with a diet high in fat has led to the current obesity epidemic. Obesity increases the risk of developing insulin resistance and type II diabetes. Excessive fat is linked to an increased production of factors that can alter the function of many organs, including skeletal muscle. The blood vessels that supply oxygen and nutrients to each organ are important in maintaining the appropriate function. Loss of these blood vessels is thought to occur in obesity, which may contribute to an increased risk of poor health outcomes. However, the underlying causes for this are not known. This proposal aims to examine the blood vessel networks within fat and muscle, and how they are affected by a long term high fat diet. We propose that an inhibitory regulatory protein (FoxO)is increased by the high fat diet, and contributes to the blood vessel loss. To test this, we will use a mouse model in which FoxO is deleted from the cells that make up blood vessels. We will determine whether lack of FoxO protein is sufficient to reverse the negative consequences of high fat diet on the blood vessels within fat and muscle. We also will consider whether loss of this protein in the high fat fed animals can improve their metabolism. These investigations will provide knowledge of how a high fat diet leads to loss of blood vessels, and new insight into ways in which these negative outcomes may be reversed. These findings may have potential clinical implications for treatment of obesity-associated complications that are linked to diabetes.
- Vitamin D3 supplementation and restriction on functional (motor performance, paw grip endurance, ability to move), disease (body condition, clinical score, disease onset, disease progression, lifespan) and skeletal muscle/central nervous system molecular outcome measures (oxidative stress, inflammation, endoplasmic reticulum stress, intracellular calcium trafficking, apoptosis, cellular redox, mitochondrial bioenergetics, contractile protein, neuron count, blood brain barrier integrity, blood spinal cord barrier integrity, neurotrophic factors) in the mouse model of amyotrophic lateral sclerosis (ALS; Lou Gehrig’s), with special emphasis on sex differences.
- Vitamin D3 and calcium supplementation in type 2 diabetic subjects on insulin resistance, glucose tolerance, glycemic control, anthropometrics, and carbohydrate and protein metabolism.
Introduction: the mitochondrial advantage for muscle and whole body health
Dr. Hood’s research program involves the study of the muscles we use for locomotion, and the energy supply to those muscles via organelles within the cells called mitochondria. Mitochondria are the “powerhouses” of the cell, and this is particularly relevant in muscles which require considerable energy during exercise. During most of our sustained activities, mitochondria are the main source of energy, or ATP. When muscles are used often, they become “trained” to the specific task, and the number and size of mitochondria increase considerably. This adaptation has been well known for years among endurance athletes, who train to reduce levels of fatigue during competition. The increase in mitochondria with training is a wonderful example of tissue “plasticity”, the ability of a tissue or organ system to adapt to the stressors (like exercise) imposed upon it. Indeed mitochondrial content in muscle can increase by 50-100% in response to regularly performed exercise.
This mitochondrial adaptation to exercise is not simply useful for endurance athletes. It has profound health implications, leading to a greater work capacity and metabolic “flexibility”. For example, an increase in mitochondria with training can enhance our ability to burn fat preferentially over carbohydrate. Even the leanest of individuals has a considerable fat store which can be oxidized, or burned, during exercise. The advantage of this fat oxidation is that the meager carbohydrate stores within our liver and muscle are “spared”, and used only when needed. This helps our endurance capacity, and prevents the build-up of fat metabolites which can accumulate in muscle. These metabolites can impair important signaling events in muscle, particularly the pathway that responds to insulin. This can lead to insulin resistance, obesity and type 2 diabetes. Thus, an increase in mitochondrial content has important health benefits in maintaining appropriate levels of lipid metabolism and preventing lipid accumulation.
Understanding the pathways of mitochondrial synthesis in muscle
Our main research program, funded by the Natural Sciences and Engineering Research Council (NSERC) of Canada and the Canada Research Chairs Program, is devoted to studying the cellular mechanisms of how mitochondria increase in muscle in response to exercise. The long-term objective is to develop a complete understanding of mitochondrial biogenesis in skeletal muscle. Biogenesis refers to the processes leading to the formation of an expanded mitochondrial network within cells, involving increases in mitochondrial content and changes in organelle composition. We use a multi-disciplinary approach to investigate this, using techniques of physiology, biochemistry, and cell and molecular biology. Our laboratory investigates how different exercise models in animals or contracting muscle cells produce signals that turn on, or turn off genes within the nucleus, to change the pattern of gene expression, leading to a healthier muscle. We are asking fundamental questions about how exercise controls the synthesis of the specific proteins which regulate the biogenesis of mitochondria. Some of these proteins include the transcriptional coactivator PGC-1α, the histone deacetylase SirT1, the transcription factor Tfam, and the tumor suppressor p53. The significance of the research is that it enhances our understanding of the functional role of mitochondria in skeletal muscle, how mitochondria adapt to exercise, and the role of exercise in treating metabolic diseases.
For publications in this area, see the following papers:
Understanding mitochondrial degradation in muscle during disuse atrophy
When muscles remain unused, they shrink in size (i.e. atrophy) and become metabolically inefficient. Muscles lose mitochondria, and endurance diminishes. How does this loss of mitochondria take place? The process of mitochondrial degradation, termed “mitophagy”, is complex, and very little is known about how it is regulated in muscle. Because mitochondria are so important for whole body metabolic rate and muscle health, our comprehension of this process is vital. Our research program in this area is funded by the Canadian Institutes of Health Research (CIHR), and it seeks to understand the molecular basis for how muscle disuse brought about by physical inactivity, neurological defects or nerve injury can affect mitophagy in muscle. Using animal and cell culture models, we also seeks to identify the possible role that exercise has in improving the maintenance and function of mitochondria resulting from disuse conditions. The significance of the research is that it helps us to understand how mitochondria are degraded, and it provokes us to seek exercise and/or pharmaceutical remedies to improve mitochondrial function in muscle.
For publications in this area, see the following papers:
Understanding the molecular basis of sarcopenia in aging muscle
Aging muscle is characterized by a loss of muscle mass, termed sarcopenia. This is evident from the degree of muscle wasting and frailty observed in older individuals, a phenomenon observed all over the world. The result is a loss of strength and endurance which can increase the susceptibility to falls and fractures. This decrease in muscle mass can be attributed to multiple causes, but an increasing amount of evidence points to an important contribution from mitochondria. Aging muscle displays a decline in mitochondrial content, and these mitochondria become fragmented with age, leading to disturbed functions. Mitochondria begin to produce increasing amounts of damaging reactive oxygen species (ROS) as we age. These ROS damage DNA and lead to cellular atrophy. The decline in mitochondrial content leads to a reduction in endurance capacity, even for everyday activities, which can affect quality of life considerably. Thus, the purpose of this CIHR-funded research program is to understand how both the synthesis and degradation of mitochondria are affected in aging muscle, and whether exercise can restore muscle mass, and mitochondrial function as we age. To accomplish this, we use several experimental models, including:
- A well-established animal model of aging, the Fischer Brown Norway rat
- Wheel running exercise models in the mouse
- Contracting and resting muscle cells in cell culture
Our working hypothesis is that exercise will improve mitochondrial content, shape, size and function in aging muscle, and thereby help to rescue the loss of muscle mass with age. This research has profound health and therapeutic implications for the use of exercise to improve the “metabolic” quality of life in aging individuals.
For publications in this area, see the following papers:
According to the Heart and Stroke Foundation of Canada, cardiovascular diseases are the primary cause of mortality in Canadian men and women and cost the Canadian government more than $20 billion/year. More women than men die from cardiovascular disease each year (41% versus 37%; Heart and Stroke Foundation of Canada), yet many physiological studies do not investigate women. My research will determine the physiological mechanisms behind the prevalence and lethality of cardiovascular disease in women and use this information to find potential avenues of treatment. Research will focus on:
- Sexually dimorphic autonomic, cardiovascular, and respiratory responses to physiological stressors and the changes in those responses due to sex and/or female sex hormones
- Determining the mechanisms behind the greater propensity of women for orthostatic hypotension (OH), postural orthostatic tachycardia syndrome (POTS), and heart failure with preserved ejection fraction (HFpEF)
- Developing potential treatments for OH, POTS, and HFpEF such as pharmaceuticals (e.g. oral contraceptives/hormone replacement) and exercise.
Some of the measurements that will be used include regional blood flow (splanchnic, renal, brain, and muscle) and muscle sympathetic nerve activity.
Obesity is a known risk factor for diabetes and cardiovascular disease (CVD), but the risk may not be the same for all obese people. Some obese individuals may actually be at lower risk for diabetes and CVD than lean people. Recent work also suggests that many people may gain weight due to factors that do not directly contribute to the "energy in" and "energy out" equation (diet and exercise). These reasons include sleep duration, environmental toxins, or that age at which your mother gave birth to you and may account for some of the differences in health seen in obese people and may influence their ability to lose weight.
The first aim of this project is to determine whether there truly is a healthy obese person. If there is, what factors protect these people from the health problems commonly seen with obesity? Do these healthy obese people benefit from weight loss? If so, how do the presence of traditional or non-traditional risk factors for obesity impact on health and the weight loss achieved?
This work will be done using two approaches. First, use of existing large datasets will allow us to answer our research questions more quickly than if we had to collect all new data. We will also be able to look at repeat visits so that we can assess changes over time, to see how different groups of people with obesity develop health conditions. Some datasets have information on causes of death so that we can also determine how different factors relate with this important outcome. Second, working with the Wharton Weight Management Centre will give us a chance to apply our research findings within an existing clinic that has a better-rounded sample than typical research weight loss studies.
If there are differences in health and weight loss potential between obese people, this work will help physicians more accurately identify high-risk patients and focus care. It will allow public health officials to improve resource planning and health care cost estimates of obesity.
Our research interest concerns the basic regulatory mechanisms involved in cellular differentiation. This work is primarily undertaken using cardiac, skeletal and smooth muscle cells and neurons as model systems and is aimed at understanding the role of transcription factors in orchestrating tissue-specific gene expression and differentiation.
The genesis of this work was in identifying DNA binding proteins that are involved in transcriptional regulation during muscle development. Subsequent work explored the mechanisms by which these factors regulate cellular gene expression and differentiation. A main focus of our work has been the molecular cloning and characterization of a family of transcription factors (four genes, labelled MEF2A-D) that regulate the expression of many cardiac, smooth and skeletal muscle specific genes via the myocyte enhancer factor 2 (MEF2) cis- element. Based on their structural similarity, these genes belong to the MADS superfamily of DNA binding proteins that are involved in cell fate specification in many organisms ranging from yeasts to humans. Since the identification of the MEF2 gene family, further studies have been undertaken to assess the biological role of these genes during cardiac and skeletal muscle differentiation as well as in a variety of post-natal contexts such as cardiac hypertrophy and muscle regeneration.Studies are also ongoing to determine the contribution of other transcriptional regulators such as the Fra2 subunit of the AP-1 complex and the Smad7 protein to the myogenic program.
This work is supported by the Canadian Institutes for Health Research (CIHR), the Natural Sciences and Engineering Research Council (NSERC) of Canada and the Heart and Stroke Foundation of Canada (HSF).
Skeletal muscle contraction requires an enormous amount of energy which is supplied mainly through carbohydrates and fats in our diet. Most of this energy is released in special organelles within muscle cells known as mitochondria which break down carbohydrates and fats through specific enzyme pathways. These enzymes must be activated rapidly during contraction and under nutritional challenges. Traditional explanations for enzyme activation include the addition of high-energy molecules, such as phosphates (phosphorylation) to specific sites on enzymes (covalent regulation) or small compounds generated during contraction or substrate catabolism, such as metabolites, to other sites (allosteric regulation). However, there is evidence for a third form of regulating enzymes which has not been examined in detail with regards to skeletal muscle metabolism: redox signaling.
Rather than changing enzyme activity through binding small molecules, redox signaling transfers energy from highly reactive chemicals known as oxidants. Many of these oxidants are produced during or after muscle contraction and nutritional challenges from multiple sources, including from blood vessels located near muscle cells, the cytoplasm within muscle cells themselves or the mitochondria as a by-product of metabolism. These oxidants (such as superoxide, hydrogen peroxide, others) change the energy state of specific amino acids known as cysteines on enzymes. Such redox signaling through cysteines is a powerful method of regulating proteins in other cell types and diseases (such as cancer) but has rarely been examined in skeletal muscle. Given that both contraction and nutrients can produce oxidants, this redox-paradigm may actually be a predominant method of regulating metabolism in muscle cells. This research may provide a new paradigm for understanding how diet and exercise regulate metabolism in skeletal muscle.
Dr. Riddell's laboratory (Exercise physiology endocrinology laboratory for the study of the metabolic syndrome and diabetes) studies the physiological effects of exercise and stress on diabetes. Work done in the lab has shown that the combination of a high fat diet and cortisol (a stress hormone) causes severe insulin resistance, fatty liver, and type 2 diabetes and that regular exercise can help prevent these effects. In another research theme, a new pharmacological agent is being developed that can help prevent exercise and insulin-induced low blood sugar in type 1 diabetes. Finally, work is now being initiated on developing a "smart pump" (or an artificial pancreas) for active people with type 1 diabetes.
The worldwide obesity epidemic represents a significant health concern as a risk factor for a wide range of diseases and complications. Fat tissue plays a crucial role in the control of weight gain. While white fat tissue stores triglyceride brown fat tissue (BAT) uses it up. Hence, one approach to minimize weight gain is to increase the amount of BAT. Notably, an amount of active BAT found in some human subjects, 63 grams, would be sufficient to burn off an amount equivalent to about 4 kg of fat during the course of one year. One approach to increase the number of brown fat cells is by manipulating their stem cell precursors. From our own and other studies it is known that the reduction of a protein called p107 forces stem cells to become brown fat cells. With this in mind we will screen compounds for their potential to induce formation of brown fat cells from stem cells. These compounds are chosen because they are within a class of molecules associated with the reduction of p107 in cells. We envision that the molecules successful in brown adipocyte formation can serve as a strategy to increase energy output to combat weight gain.