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Weight loss through dietary energy restriction (ER) is an effective method to promote fat mass loss. However, a negative consequence of ER is the loss of lean body mass (LBM), particularly skeletal muscle, which is induced by an imbalance between rates of muscle protein synthesis (MPS) and muscle protein breakdown (MPB). Increased protein intake and resistance exercise (RE) during ER promote the retention of LBM. Currently, the relative contribution of MPS and MPB to diet-induced LBM loss, and the effect of protein intake and RE on these variables is not well characterized. In Study 1 we compared the acute (hour-to-hour) MPS response to the ingestion of whey and soy protein, before and after 14 days of ER (-750kcal/d). The results of Study 1 indicated that whey protein was superior to soy protein in stimulating MPS before and after ER. In Studies 2 and 3 we examined the effect of 10 days of a marked 40% energy restriction on acute postabsorptive MPS and MPB and integrated (day-to-day) MPS. Using unilateral RE, we examined the effects of protein (1.2g protein/kg/g or 2.4g protein/kg/d) at rest and in combination with resistance exercise. The results of Study 2 showed that there were no changes in acute MPB or markers of proteolysis with ER. The results of Study 3 indicated that acute and integrated MPS were reduced following ER at both protein levels (1.2g protein/kg/g or 2.4g protein/kg/d), but RE was able to prevent this decline. Taken together, these studies demonstrate that reductions in MPS are the likely reason for LBM loss during short-term dietary energy restriction, and strategies such as RE and high quality protein intake can help to prevent the decline in MPS. These findings provide information for the design of weight loss programs that wish to preserve skeletal muscle. / Thesis / Doctor of Philosophy (PhD) / Dietary energy restriction is commonly used to promote weight/fat loss; however, a potential negative consequence of dietary energy restriction is the loss of skeletal muscle mass. This thesis examines the impact of dietary energy restriction on the two processes that regulate skeletal muscle mass: muscle protein synthesis and muscle protein breakdown. Additionally, this thesis investigates the role of protein intake and resistance exercise as strategies to prevent diet-induced changes in muscle protein synthesis and breakdown. The studies within this thesis demonstrate that during energy restriction rates of muscle protein synthesis are reduced whilst muscle protein breakdown is unchanged. Importantly, consuming high quality protein such as whey protein and performing resistance exercise prevent the diet-induced decline in rates of muscle protein synthesis. These findings provide new and insightful information for the design of weight loss programs that aim to preserve skeletal muscle whilst also promoting the loss of body fat.

Exercise has been shown to influence nearly every tissue type in the body, including the hematopoietic system. The means by and the extent to which exercise is able to do this is unknown. Here, we investigated the effects of skeletal muscle and exercise on several components of hematopoiesis. Firstly, we investigated exercise induced changes in skeletal muscle endocrine signalling. We demonstrated that exercise increased skeletal muscle hypoxia, leading to HIF1α and HIF2α stability, resulting in increased expression of erythropoietin. As well, myoblasts in culture were shown to express and release erythropoietin in response to hypoxia. Secondly, we measured mobilization of hematopoietic cells during exercise. We demonstrated that exercise greatly increased the number of hematopoietic stem cells in circulation. The quantity of mobilization was dependent on exercise intensity, did not depend on fitness levels, and was at peak immediately post exercise. Thirdly, we measured levels of extramedullary hematopoiesis following exercise. Exercise increased spleen hematopoietic stem cell content. Furthermore, expression of genes associated with hematopoietic homing, adhesion, quiescence, and growth were all increased in the spleen following exercise. Finally, we examined bone marrow in the appendicular and axial skeleton of aged animals. Here, exercise increased bone marrow cellularity and reduced bone marrow adiposity in the appendicular skeleton of aged mice. However, lumbar vertebral marrow cellularity and skeletal muscle expression of hematopoietic cytokines in these mice was unaffected by exercise. Taken together, these results demonstrate that exercise is a potent mediator of hematopoietic homeostasis. Several themes recurrent in these and other studies lead to insight in how exercise is able to exert influence on hematopoiesis, namely: tissue specific changes in hematopoietic growth and homing factor expression, the ability of mechanical forces felt during exercise to alter the bone marrow niche microenvironment, and increased flux of hematopoietic stem cells through their various bodily niches. / Thesis / Doctor of Philosophy (PhD) / Exercise affects many different tissue types throughout the body. The hematopoietic system, through which the body produces blood cells, is no exception. How exercise as a stimulus is able to influence this system is poorly understood. Here, we demonstrate that exercise is able to stimulate skeletal muscle to produce erythropoietin, a potent hematopoietic growth factor. As well, we demonstrate that exercise is capable of mobilizing hematopoietic stem cells from the bone marrow to the blood. We then describe how exercise is able to increase hematopoietic activity outside the bone marrow. Finally, we show that exercise affects marrow in only certain bone marrow cavities. Our findings demonstrate that exercise is able to influence hematopoiesis in a myriad of ways. As well, our findings highlight potential commonalities in the means by which exercise exerts these influences.

Skeletal muscle possesses a remarkable plasticity, able to repair, remodel and adapt to various stressors. A population of resident muscle stem cells, commonly referred to as satellite cells (SC), are largely responsible for skeletal muscle plasticity. The loss of muscle mass and plasticity typically observed in aging has been attributed to the deterioration of SC function. SC reside in a quiescent state, but following stimuli they become active, proliferate and eventually differentiate, fusing to existing muscle fibres. The progression of SC through this process, termed the myogenic program, is orchestrated by a complex network of transcription factors, termed myogenic regulatory factors. SC function is regulated by various growth factors and/or cytokines. The delivery of these signalling factors to SC is, in part, dependent on their proximity and exposure to local microvascular blood flow. The purpose of this thesis was to examine the relationship between skeletal muscle capillaries and muscle SC. We examined the effect of age on the spatial relationship between SC and muscle fiber capillaries, and observed that type II muscle fiber SC were located at a greater distance from the nearest capillary in older men as compared to their younger counterparts. We then examined the changes in SC activation status following a single bout of resistance exercise, prior to and following a 16wk progressive resistance training (RT) program. We observed that following RT, there was an enhanced SC activation in response to a single bout of resistance exercise. This enhanced response was accompanied by an increase in muscle capillarization following training. Furthermore, we investigated the impact of muscle fiber capillarization on the expansion and activation status of SC in acute response to muscle damaging exercise in healthy young men. We observed that muscle capillarization was positively related to SC pool activation and expansion. Taken together, we demonstrate that muscle capillarization may be related to the SC response following acute resistance exercise or exercise-induced injury, and may be implicated in adaptation to RT. Furthermore, the spatial relationship between muscle capillaries and SC is negatively altered by aging. / Thesis / Doctor of Philosophy (PhD) / Skeletal muscle health is, in part, maintained by a population of stem cells associated with individual muscle fibres. When muscle is damaged or stressed, these cells become activated, aid in muscle repair, and help drive adaptations to exercise. The central purpose of this thesis was to examine the relationship between muscle capillaries and muscle stem cells, and determine how that relationship impacts muscle stem cell function. We demonstrated that muscle stem cells and capillaries exist in close proximity to each other in skeletal muscle. We observed that a greater muscle capillarization is linked to improved muscle stem cell function during muscle repair. However, we also report that the distance between muscle capillaries and muscle stem cells becomes greater in aging, and may be a root cause of impaired muscle stem cell function in aging.

A gender difference in absolute muscle strength is well documented. The extent to which quantitative (fiber area and number) and qualitative (specific tension) differences in muscle contribute to this is not well understood. The purpose of this study was to examine a variety of muscle characteristics in the biceps brachii and vastus lateralis in a sample of males (n=8) and females (n=8) with a wide range of training histories. Measurements included motor unit number, size and activation, and voluntary strength of the elbow flexors and knee extensors. Fiber characteristics were determined from needle biopsies and muscle areas by computerized tomographical scanning. Females were approximately 52% and 66% as strong as the males in the upper and lower body respectively. A significant (p ≤ .05) correlation was found between strength and muscle cross-sectional area. Females had 45, 41, 30 and 25% smaller muscle cross-sectional areas for the biceps brachii, total elbow flexors, vastus lateralis and total knee extensors respectively (p ≤ .01). No significant gender difference was found in the strength to cross-sectional area ratio for elbow flexion and knee extension. Males had significantly larger type I fiber areas (4597 vs. 3483 um² ) and mean fiber areas (6632 vs. 3963 um² ) than females in biceps brachii (p ≤ .05) and significantly larger type II fiber areas (7700 vs. 4040 um²) and mean fiber areas (7070 vs. 4290 um²) in the vastus lateralis (p ≤ .05). The difference in type II fiber area in the biceps brachii was not statistically significant despite the fact that these fibers were almost twice as large in the males as in the females (8207 vs. 4306 um²). No significant gender difference was found in biceps fiber number (180,620 vs. 156,872) or muscle area to fiber area ratio in the vastus lateralis (451,468 vs. 465,007). No significant gender differences were found in any of the motor unit characteristics. The results indicate that the primary determinant of the greater muscle strength of males is their larger mean fiber areas which results in greater muscle cross-sectional areas. / Thesis / Master of Science (MSc)

Lactate removal by inactive skeletal muscle was investigated using an isolated rat hindlimb perfusion model under conditions simulating recovery from maximal exercise. The purpose of this investigation was threefold: 1) to quantify the contributions of the oxidative, glyconeogenic, and triacylgylcerol (TG) synthesis pathways to lactate (La) removal, 2) to examine differences in La removal patterns in inactive skeletal muscle of various fiber types, and 3) to investigate the possible mechanisms for La and H⁺ removal by inactive muscle. Male Sprague-Dawley rats were perfused for 60 min, at rest with either a normal perfusate (NP) (N = 8) or a lactacidotic perfusate (LP) (N = 8). The LP perfusate was characterized by elevated concentrations of La (11.0 mMol), K⁺ (7.88 mMol), and hemoglobin (16.7 g·dl⁻¹) and a decreased pH (7.15). Arterial and venous perfusate and soleus (SOL), plantaris (PLT), and white gastrocnemius (WG) muscles were analyzed for various metabolite and ion concentrations. Analysis revealed increased rates of La uptake, glycerol release and C0₂ output in the LP versus the NP group. No difference was observed for O₂ uptake or glucose uptake between the two groups. Tissue anajysis revealed no significant change in muscle ATP, CP, glycogen, pyruvate, F-6-P or TG concentration pre versus post perfusion in both LP and NP groups. Significant increases were found in muscle La concentration (pre vs post and LP vs NP), with SOL having the highest concentration followed by PLT and WG. Muscle [F-1 ,6-diP], F-1 ,6-diP /F-6-P and pyruvate/F-1 ,6-diP ratios were elevated following LP perfusion indicating glyconeogenic inhibition. Muscle glucose levels decreased in the NP but not LP group, indicating a possible shift in substrate utilization in the LP group. In the LP group, total calculated La uptake by the 3 muscles was 61.0 umole, with 14% accumulating as tissue La post perfusion. Of the remaining 86%, 12-33% could be accounted for by oxidative metabolism, and 5-7% may have been involved in glycerol release. The remaining 60-75% was unaccounted for, but was hypothesized to have been involved in carbon cycling along the glycolytic/glyconeogenic pathway and/or in TG/FFA substrate cycling. No evidence was found of net glycogen synthesis from La. Increased H⁺ and K⁺ influx and HCO₃⁻ efflux were observed in response to lactacidotic perfusion. Sodium and Cl⁻ exchange patterns showed a net influx over 60 min of LP perfusion. Data from the ionic flux of the various strong ions and non-volatile H⁺ suggested that La is transported into inactive skeletal muscle by various mechanisms, including HLa diffusion, La/H⁺ cotransport, and possibly La/Cl⁻ exchange. The data also suggested that a number of regulatory mechanisms are activated in rat skeletal muscle to maintain intracellular [H⁺] and membrane potential during lactacidotic perfusion. From this investigation it was concluded that, in inactive muscle of the isolated rat hindlimb perfused for 60 min with a lactacidotic perfusate, patterns of La uptake and metabolic elimination are different from those previously observed for active muscle. The metabolic fates of La appear to be related to the ionic disturbances associated with La and H⁺ influx into inactive muscle. The net ionic movements across the inactive hindlimb appear to be related to the preferred metabolic pathways of La elimination, but whether or not a direct cause and effect relationship exists cannot be stated conclusively. / Thesis / Master of Science (MSc)

A manual method of estimating the number of functional motor units within a selected muscle has been implemented as an automatic system. The system has been developed in FORTRAN 77 on a PDP-11/34 minicomputer. This system employs closed loop control of the stimulator, thus eliminating any active role of the operator during the testing. The heuristic decision-making processes required of the operator in the manual method have been analyzed and replaced with a defined algorithm incorporating quantifiable decision criteria. The automated motor unit counting system has been demonstrated using a number of human subjects. The system is suitable for use in a research clinical environment, providing a flexible tool for clinical trials or for further development of the technique. / Thesis / Master of Engineering (MEngr)