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The molecular pathogenesis of skeletal muscle atrophyBongers, Kale Stephen 01 May 2016 (has links)
Skeletal muscle atrophy is a debilitating condition that commonly occurs as a secondary consequence of many acute and chronic medical conditions, including muscle disuse, heart and renal failure, starvation, cancer, HIV/AIDS, and aging. Though it leads to weakness, falls, and fractures, and reduces independence and quality of life for millions of Americans annually, no effective pharmacologic therapies for muscle atrophy exist. This is largely due to a poor understanding of the pathogenesis of skeletal muscle atrophy at a molecular level. In this thesis, I describe my studies into the molecular pathogenesis of skeletal muscle atrophy. Using mouse models, I showed that the gene encoding the pro-atrophy nuclear protein Gadd45a is regulated by distinct pathways after muscle denervation and fasting, and also identified a novel protein regulating skeletal muscle fiber size.
First, we demonstrated that denervation-induced muscle atrophy, unlike atrophy mediated by fasting, does not require the bZIP transcription factor ATF4. However, the lysine deacetylase HDAC4 is sufficient to induce Gadd45a mRNA and necessary for Gadd45a mRNA induction after denervation, but not after fasting. Taken together, these data show that Gadd45a is a central convergence point for muscle atrophy caused by several stimuli, and also demonstrate that distinct pathways mediate Gadd45a induction in different models of skeletal muscle atrophy.
Second, we identified spermine oxidase as a critical regulator of muscle fiber size. We observed that spermine oxidase mRNA and spermine oxidase protein were reduced by several distinct causes of muscle atrophy (i.e. immobilization, denervation, fasting, and aging). Furthermore, spermine oxidase overexpression increased muscle fiber size, while spermine oxidase knockdown caused muscle fiber atrophy. Restoring spermine oxidase expression significantly attenuated muscle atrophy after limb immobilization, denervation, and fasting. Finally, we identified p21 as a key upstream regulator of spermine oxidase expression, and spermine oxidase as a required mediator of p21-mediated skeletal muscle fiber atrophy.
Collectively, these findings greatly advance our understanding of the molecular pathogenesis of skeletal muscle atrophy. These data demonstrate that Gadd45a is a convergence point for multiple pro-atrophy pathways and identify spermine oxidase as a novel therapeutic target for the treatment of skeletal muscle atrophy. These discoveries suggest several important new areas for future research, and further our understanding of this common, debilitating condition.
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Therapeutic interventions for lipidinduced insulin resistance in skeletal muscle: mechanisms of actionLessard, Sarah, not supplied January 2006 (has links)
It has long been known that in addition to disruptions in glucose homeostasis, individuals with insulin resistance have a breakdown in lipid dynamics, often manifested by elevated levels of circulating fatty acids (FA) together with accumulation of lipids in insulin-sensitive tissues, including skeletal muscle. However, little is known about how common therapies used to treat insulin resistant individuals (such as Rosiglitazone and exercise training) improve skeletal muscle lipid and glucose metabolism. Thus, the primary aim of the studies undertaken for this thesis was to enhance our understanding of the mechanisms by which Rosiglitazone and exercise training improve skeletal muscle lipid metabolism and insulin sensitivity in two distinct models of insulin resistance. The first investigation determined the effect of chronic Rosiglitazone treatment on the accumulation of lipid metabolites and enzymatic regulators of lipid metabolism in the skeletal muscle of obese Zucker rats. The observation that Rosiglitazone treatment exacerbated the accumulation of muscle ceramide and diacylglycerol in skeletal muscle, while improving glucose tolerance led to the conclusion that this insulin sensitising drug improves insulin sensitivity by mechanisms other than reduction of fatty acid metabolites in this tissue. Accordingly, the second investigation sought to identify an alternative mechanism by which Rosiglitazone treatment may improve skeletal muscle insulin sensitivity. It was found that Rosiglitazone restored AMP-activated protein kinase (AMPK) á2 activity in the skeletal muscle of obese Zucker rats, providing a potential peroxisome proliferator activated receptor (PPAR) ã-independent mechanism by which this drug may mediate its insulinsensitising actions. The final experiment undertaken for this thesis determined the independent and interactive effects on Rosiglitazone and exercise training on various aspects of skeletal muscle glucose and lipid metabolism in a model of diet-induced insulin resistance, the high-fat fed rat. Exercise training, but not Rosiglitazone treatment restored skeletal muscle insulin sensitivity in high-fat fed rats. Improvements in insulin sensitivity with exercise training were associated with increased FA oxidation, increased AMPK activity and a normalisation of the expression of the Akt substrate, AS160. In contrast, Rosiglitazone treatment was associated with increased FA uptake and decreased insulin-stimulated glucose uptake in skeletal muscle. Exercise prevented the accumulation of skeletal muscle lipids in Rosiglitazone-treated animals when the two treatments were combined. In summary, the results from the studies undertaken for this thesis provide novel information regarding the mechanisms by which two insulinsensitising therapies, exercise training and Rosiglitazone treatment, act to improve glucose and lipid metabolism in skeletal muscle.It has long been known that in addition to disruptions in glucose homeostasis, individuals with insulin resistance have a breakdown in lipid dynamics, often manifested by elevated levels of circulating fatty acids (FA) together with accumulation of lipids in insulin-sensitive tissues, including skeletal muscle. However, little is known about how common therapies used to treat insulin resistant individuals (such as Rosiglitazone and exercise training) improve skeletal muscle lipid and glucose metabolism. Thus, the primary aim of the studies undertaken for this thesis was to enhance our understanding of the mechanisms by which Rosiglitazone and exercise training improve skeletal muscle lipid metabolism and insulin sensitivity in two distinct models of insulin resistance. The first investigation determined the effect of chronic Rosiglitazone treatment on the accumulation of lipid metabolites and enzymatic regulators of lipid metabolism in the skeletal muscle of obese Zucker rats. The observation that Rosiglitazone treatment exacerbated the accumulation of muscle ceramide and diacylglycerol in skeletal muscle, while improving glucose tolerance led to the conclusion that this insulin sensitising drug improves insulin sensitivity by mechanisms other than reduction of fatty acid metabolites in this tissue. Accordingly, the second investigation sought to identify an alternative mechanism by which Rosiglitazone treatment may improve skeletal muscle insulin sensitivity. It was found that Rosiglitazone restored AMP-activated protein kinase (AMPK) á2 activity in the skeletal muscle of obese Zucker rats, providing a potential peroxisome proliferator activated receptor (PPAR) ã-independent mechanism by which this drug may mediate its insulinsensitising actions. The final experiment undertaken for this thesis determined the independent and interactive effects on Rosiglitazone and exercise training on various aspects of skeletal muscle glucose and lipid metabolism in a model of diet-induced insulin resistance, the high-fat fed rat. Exercise training, but not Rosiglitazone treatment restored skeletal muscle insulin sensitivity in high-fat fed rats. Improvements in insulin sensitivity with exercise training were associated with increased FA oxidation, increased AMPK activity and a normalisation of the expression of the Akt substrate, AS160. In contrast, Rosiglitazone treatment was associated with increased FA uptake and decreased insulin-stimulated glucose uptake in skeletal muscle. Exercise prevented the accumulation of skeletal muscle lipids in Rosiglitazone-treated animals when the two treatments were combined. In summary, the results from the studies undertaken for this thesis provide novel information regarding the mechanisms by which two insulinsensitising therapies, exercise training and Rosiglitazone treatment, act to improve glucose and lipid metabolism in skeletal muscle.
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Muscle Thixotropy : Implications for Human Motor ControlAxelson, Hans January 2005 (has links)
<p>Human skeletal muscles possess thixotropic, i.e. history-dependent mechanical properties. This means that the degree of passive muscle stiffness and resting tension is dependent on the immediately preceding history of contractions and length changes. Athletes, for instance, reduce passive muscle stiffness by various types of ‘limbering-up’ procedures, whereas muscle stiffness gradually increases during inactivity.</p><p>Passive resistance of antagonistic muscles may significantly add to the total load during voluntary muscle contractions. This resistance may vary from one moment to another, depending on immediately preceding events. This research was conducted to determine whether history-dependent variations in passive muscular forces influence motor control of voluntary joint movements and steady maintenance of joint positions in healthy subjects. </p><p>In study I, the EMG signal revealed motor compensations for history-dependent variations in passive stiffness of the antagonists during slow voluntary wrist joint movements. Studies II and III demonstrated that the voluntary muscle activity required to maintain a certain wrist joint position was highly influenced by previous changes in forearm muscle length and contractions. Study IV showed that rapid voluntary movements varied in speed and onset time depending on the prevailing degree of muscle resistance, and in addition that the central nervous reaction time required to execute rapid movements was highly influenced by immediately preceding muscle-conditioning procedures.</p><p>History-dependent variations in passive muscular forces seem to be effectively compensated by the motor control system. Presumably, voluntary motor commands to the muscles are automatically adjusted in strength to history-dependent changes in passive muscular forces. Such adjustments occur within the central nervous system, which receives information about the mechanical state of the muscles. Several issues in connection with muscle thixotropy remain unaddressed. For instance, do alterations in the normal thixotropic mechanical behaviour of the muscles impose a particular problem in patients with certain neuromuscular diseases? </p>
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Zebrafish embryos exposed to alcohol undergo abnormal development of motor neurons and muscle fibersSylvain, Nicole J. 11 1900 (has links)
Children with Fetal Alcohol Spectrum Disorder have significantly delayed motor skills, and deficiencies in reflex development. The reasons underlying these motor deficits are not fully understood. The purpose of this thesis was to investigate the effect of embryonic exposure to ethanol (EtOH) on motor neuron and muscle fiber morphology and physiology in zebrafish. We observed that EtOH-exposed fish took longer to hatch and exhibited fewer swimming bouts in response to touch. Immunolabelling of motor neurons indicated that EtOH-exposed fish had significantly higher rates of motor neuron axon defects. Examination of muscle fiber morphology revealed that EtOH exposure resulted in significantly smaller muscle fibers. Miniature endplate current (mEPC) recordings from muscle fibers revealed that event amplitudes, rise times, half widths, frequencies and decay times were affected by EtOH exposure. These findings indicate that motor neurons and muscle fibers of zebrafish are affected by embryonic EtOH exposure, which may be related to deficits in locomotion. / Physiology, Cell and Developmental biology
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Muscle Thixotropy : Implications for Human Motor ControlAxelson, Hans January 2005 (has links)
Human skeletal muscles possess thixotropic, i.e. history-dependent mechanical properties. This means that the degree of passive muscle stiffness and resting tension is dependent on the immediately preceding history of contractions and length changes. Athletes, for instance, reduce passive muscle stiffness by various types of ‘limbering-up’ procedures, whereas muscle stiffness gradually increases during inactivity. Passive resistance of antagonistic muscles may significantly add to the total load during voluntary muscle contractions. This resistance may vary from one moment to another, depending on immediately preceding events. This research was conducted to determine whether history-dependent variations in passive muscular forces influence motor control of voluntary joint movements and steady maintenance of joint positions in healthy subjects. In study I, the EMG signal revealed motor compensations for history-dependent variations in passive stiffness of the antagonists during slow voluntary wrist joint movements. Studies II and III demonstrated that the voluntary muscle activity required to maintain a certain wrist joint position was highly influenced by previous changes in forearm muscle length and contractions. Study IV showed that rapid voluntary movements varied in speed and onset time depending on the prevailing degree of muscle resistance, and in addition that the central nervous reaction time required to execute rapid movements was highly influenced by immediately preceding muscle-conditioning procedures. History-dependent variations in passive muscular forces seem to be effectively compensated by the motor control system. Presumably, voluntary motor commands to the muscles are automatically adjusted in strength to history-dependent changes in passive muscular forces. Such adjustments occur within the central nervous system, which receives information about the mechanical state of the muscles. Several issues in connection with muscle thixotropy remain unaddressed. For instance, do alterations in the normal thixotropic mechanical behaviour of the muscles impose a particular problem in patients with certain neuromuscular diseases?
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Ultrasonic Quantification of Skeletal Muscle Dynamics : Feasibility and LimitationsLindberg, Frida January 2013 (has links)
Pain and disorders of the human skeletal muscles are one of the most common reasons for medical consultations in the western countries today and there is a great need to improve both the understanding and treatment of several different muscular conditions. Techniques describing the muscle function in vivo are often limited by either their invasiveness or lack of spatial resolution. Electromyography (EMG) is the most common approach to assess the skeletal muscle function in vivo, providing information on the neurological input. However, the spatial resolution is in general limited and there are difficulties reaching deep musculature without using invasive needles. Moreover, it does not provide any information about muscle structure or mechanical aspects. Quantitative ultrasound techniques have gained interest in the area of skeletal muscles and enables non-invasive and in-vivo insight to the intramuscular activity, through the mechanical response of the activation. However, these techniques are developed and evaluated for cardiovascular applications and there are important considerations to be made when applying these methods in the musculoskeletal field. This thesis is based on the work from four papers with the main focus to investigate and describe some of these considerations in combination with the development of processing and analyzing methods that can be used to describe the physiological characteristics of active muscle tissue. In the first paper the accuracy of the Doppler based technique Tissue Velocity Imaging (TVI) was evaluated in a phantom study for very low tissue velocities and the effect of the pulse repetition frequency was considered. The second paper presents a biomechanical model to describe the TVI strain’s dependency on the muscle fiber pennation angle. In the third and fourth papers the intramuscular activity pattern was assessed through the regional tissue deformation by motion mode (M-mode) strain imaging. The activity patterns were analyzed during force regulation and for the effects of fatigue. The work of this thesis show promising results for the application of these methods on skeletal muscles and indicate high clinical potential where quantitative ultrasound may be a valuable tool to reach a more multifaceted and comprehensive insight in the musculoskeletal function. However, the methodological considerations are highly important for the optimized application and further evaluation and development of analyzing strategies are needed. / <p>QC 20130516</p>
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The Role of XRCC1 in the Repair of DNA Strand Breaks in Skeletal Muscle DifferentiationBurns, Leanne E. 22 September 2011 (has links)
Caspase-3 has demonstrated a non-apoptotic function in several developmental programs including skeletal muscle differentiation, yet the mechanism of action has not been fully elucidated. Under apoptotic conditions Caspase-3 induces DNA fragmentation through activation of CAD. Recent observations have demonstrated CAD activity and the resulting DNA strand breaks are also vital for skeletal muscle differentiation. These breaks are transient in nature, suggesting an active DNA repair program to maintain genomic integrity. The aim of this study was to delineate the DNA repair mechanism coordinated with caspase/CAD mediated DNA damage. It was found that XRCC1 formed punctate nuclear foci early in myoblast differentiation concurrent to the induction of DNA damage. Caspase-3 inhibition caused attenuation of the formation of DNA lesions and XRCC1 foci in differentiating myoblasts. Targeted reduction in XRCC1 expression impaired myoblast differentiation. These results suggest that XRCC1 may play a role in repairing the DNA damage associated with myoblast differentiation.
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Myocyte Androgen Receptor Modulates Body Composition and Metabolic ParametersFernando, Shannon M. 31 December 2010 (has links)
Androgens (such as testosterone) have been shown to increase lean body mass and reduce fat body mass in men through activation of androgen receptors (AR). While this suggests a potential clinical use for androgens, attempts at utilization of this class of hormones as a therapeutic are limited by side effects due to indiscriminate AR activation in various tissues. Thus, a greater understanding of the tissues and cells involved in promoting these changes would be beneficial. Here we show that selective overexpression of AR in muscle cells of transgenic (HSA-AR) rodents both increases lean muscle mass and significantly reduces fat mass in males. Similar effects can be induced in HSA-AR females treated with testosterone. Metabolic analyses of HSA-AR males show that these animals demonstrate increased O2 consumption and hypermetabolism. Thus, targeted activation of AR in muscle regulates body composition and metabolism, suggesting a novel target for drug development.
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Myocyte Androgen Receptor Modulates Body Composition and Metabolic ParametersFernando, Shannon M. 31 December 2010 (has links)
Androgens (such as testosterone) have been shown to increase lean body mass and reduce fat body mass in men through activation of androgen receptors (AR). While this suggests a potential clinical use for androgens, attempts at utilization of this class of hormones as a therapeutic are limited by side effects due to indiscriminate AR activation in various tissues. Thus, a greater understanding of the tissues and cells involved in promoting these changes would be beneficial. Here we show that selective overexpression of AR in muscle cells of transgenic (HSA-AR) rodents both increases lean muscle mass and significantly reduces fat mass in males. Similar effects can be induced in HSA-AR females treated with testosterone. Metabolic analyses of HSA-AR males show that these animals demonstrate increased O2 consumption and hypermetabolism. Thus, targeted activation of AR in muscle regulates body composition and metabolism, suggesting a novel target for drug development.
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Contribution of sarcoplasmic reticulum calcium pumping to resting mouse muscle metabolismNorris, Sarah January 2009 (has links)
Few studies have quantified resting mouse muscle metabolism and even fewer studies have separated the contribution of sarcoplasmic reticulum (SR) Ca2+ pumping to resting metabolic rate. Furthermore, the studies that have attempted to quantify the contribution of Ca2+ pumping have used indirect methods to inhibit SR Ca2+ ATPase activity. The purpose of this study is to directly quantify resting muscle oxygen consumption and the contribution of SR Ca2+ pumping to resting oxygen consumption in mouse hindlimb muscles by using CPA to specifically inhibit Ca2+ pump activity in intact muscles at rest. The TIOX system was used to measure resting muscle VO2 of extensor digitorum longus (EDL) and soleus (SOL) muscles at 30oC and 20oC. C57BL mice aged 8-12 weeks were used with an average whole body mass of 23.8 g and EDL and SOL dry weights averaging 1.88 mg and 1.8 mg, respectively. All muscle VO2 measurements are expressed per gram dry weight. There were no differences (P>0.1) in resting muscle VO2 between EDL and SOL muscles at either 30oC (EDL, 2.05 µL/g/s; SOL, 2.27 µL/g/s) or 20oC (EDL, 0.62 µL/g/s; SOL, 0.71 µL/g/s). The average Q10 (3.1) was determined from EDL and SOL VO2 measures at 20oC and 30oC. The contribution of Ca2+ pumping by the sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) was measured at 30oC using a range of CPA concentrations (1-15 µM) . There was a concentration-dependent effect of CPA on oxygen consumption with increasing CPA concentrations up to 10 µM resulting in progressively greater reductions in muscle oxygen consumption. Specifically, 1, 5, 10, and 15 µM CPA caused an 11, 35.4, 49.5, and 50.3% reduction in VO2. There were no differences (P>0.1) between 10 and 15 µM CPA indicating that 10 µM CPA induces maximal inhibition of SERCA in isolated muscle preparations. The results indicate that the Ca2+ pumping by SERCA is responsible for ~50% of oxygen consumption in resting mouse EDL and SOL muscle. This is the first study to use a direct inhibitor of SERCA to quantify the contribution of Ca2+ cycling to resting oxygen consumption and therefore is a more accurate reflection of the actual contribution of SERCA to resting muscle oxygen consumption compared to previous findings. These results suggest that SERCA energy consumption accounts for a large portion of resting muscle metabolism and may represent a potential therapeutic target for metabolic alterations to oppose obesity.
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