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group_1_presentation_3_-_muscular_dystrophy [2016/11/28 16:53]
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group_1_presentation_3_-_muscular_dystrophy [2018/01/25 15:18] (current)
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 ===== Pathophysiology ===== ===== Pathophysiology =====
    
-<style float-right>​ +Muscle ​biopsies ​of patients diagnosed ​with DMD typically exhibit ​necrotic ​or degenerating ​muscle fibers, which often manifest in aggregate forms, and observable decreases in muscle fiber diameter ​(Deconinck & Dan, 2007)These necrotic fibers are surrounded by several ​macrophages and lymphocytes. ​During the early stages of the disease, ​small, immature ​muscle ​fibers ​are observed, which shows muscle regeneration ​from myoblasts, leading to a balance between necrosis and regeneration ​during ​these early phases. However, as the disorder progresses, the capacity ​of the muscle fibers to regenerate is greatly diminished; as a result, worn-out muscle fibers are gradually replaced with connective and adipose ​tissues. Thus, the symptomatical manifestations of DMD are due to the underlying imbalance between muscle fiber degeneration and myoblast regeneration,​ with the foremost pathologic feature being muscle ​tissue ​necrosis. In addition, studies on animal models of DMD suggest ​that the regenerative capability of the muscle ​fibers ​significantly decline with age of the individual (Deconinck & Dan, 2007).
-{{:​screen_shot_2016-11-28_at_4.51.04_pm.png|Figure 2: Muscle ​biopsy ​of an individual ​with DMD. The * shows necrotic muscle fibers, which aggregates with other degenerating fibers, and shows a decreased ​muscle fiber diameter ​compared to healthy fibersThe arrow shows macrophages and lymphocytes ​that surround the necrotic fibers (or start to surround healthy muscle fibers)The ^ shows small, immaturefibers ​that arise from myoblasts during ​the early stages ​of the disease. The x shows connective and adipose tissue that replace worn-out ​fibers.}}+
  
-    Figure 2Muscle biopsy of an individual with DMDThe * shows necrotic muscle fibers, +<style float-center>​ 
-    which aggregates with other degenerating fibers, and shows a decreased muscle fiber  +{{ :screen_shot_2016-11-28_at_4.51.04_pm.png |}}
-    diameter compared to healthy fibersThe arrow shows macrophages and lymphocytes  +
-    that surround the necrotic fibers (or start to surround healthy muscle fibers). The ^ shows  +
-    small, immature, fibers that arise from myoblasts during the early stages of the disease.  +
-    The x shows connective and adipose tissue that replace worn-out fibers.+
  
-</style>+//Figure 2: Muscle biopsy of an individual with DMD. The * shows necrotic muscle fibers, which aggregates with other degenerating fibers, and shows a decreased muscle fiber diameter compared to healthy fibers. The arrow shows               ​macrophages and lymphocytes that surround the necrotic fibers (or start to surround healthy muscle fibers). The ^ shows small, immature, fibers that arise from myoblasts during the early stages of the disease. The x shows connective and adipose tissue that replace worn-out fibers.//
  
-Muscle biopsies of patients diagnosed with DMD typically exhibit necrotic or degenerating muscle fibers, which often manifest in aggregate forms, and observable decreases in muscle fiber diameter (Deconinck & Dan, 2007). These necrotic fibers are surrounded by several macrophages and lymphocytes. During the early stages of the disease, small, immature muscle fibers are observed, which shows muscle regeneration from myoblasts, leading to a balance between necrosis and regeneration during these early phases. However, as the disorder progresses, the capacity of the muscle fibers to regenerate is greatly diminished; as a result, worn-out muscle fibers are gradually replaced with connective and adipose tissues. Thus, the symptomatical manifestations of DMD are due to the underlying imbalance between muscle fiber degeneration and myoblast regeneration,​ with the foremost pathologic feature being muscle tissue necrosis. In addition, studies on animal models of DMD suggest that the regenerative capability of the muscle fibers significantly decline with age of the individual (Deconinck & Dan, 2007). 
  
 +</​style>​
  
 There are several hypothesized mechanisms that are proposed to lead to the muscle fiber necrosis seen in DMD (Deconinck & Dan, 2007): There are several hypothesized mechanisms that are proposed to lead to the muscle fiber necrosis seen in DMD (Deconinck & Dan, 2007):
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 **1.Mechanical Hypothesis.** Dystrophin-associated protein complexes and additional proteins normally form lattice-like structures, called costamers, on the sarcolemmal cytoplasm. These costamers anchor the cytoskeleton components, such as the actin/​myosin filaments, to the extracellular matrix, thereby maintaining the integral structure of the muscle fiber. In addition, costamers serve as mechanical couplers to distribute contractile forces generated in the sarcomere. The costamers are connected to the cytoskeleton components through the dystrophin protein. In individuals with DMD, mutations in the dystrophin gene lead to dysfunctional or insufficient copies (or lack thereof) of the dystrophin protein, which causes a delocalization of the dystrophin-associated proteins and thus alterations in the sarcolemmal membrane structure. This phenomenon underlies muscle fiber membrane fragility, as the cytoskeletal fragments lose their attachment to the membrane, leading to a disintegration of the integral framework and the internal contractile components of the muscle fiber. In addition, the ability to sustain eccentric muscular contractions appears to be drastically reduced in individuals with DMD (which serves as an indication of muscle weakness) compared to controls. **1.Mechanical Hypothesis.** Dystrophin-associated protein complexes and additional proteins normally form lattice-like structures, called costamers, on the sarcolemmal cytoplasm. These costamers anchor the cytoskeleton components, such as the actin/​myosin filaments, to the extracellular matrix, thereby maintaining the integral structure of the muscle fiber. In addition, costamers serve as mechanical couplers to distribute contractile forces generated in the sarcomere. The costamers are connected to the cytoskeleton components through the dystrophin protein. In individuals with DMD, mutations in the dystrophin gene lead to dysfunctional or insufficient copies (or lack thereof) of the dystrophin protein, which causes a delocalization of the dystrophin-associated proteins and thus alterations in the sarcolemmal membrane structure. This phenomenon underlies muscle fiber membrane fragility, as the cytoskeletal fragments lose their attachment to the membrane, leading to a disintegration of the integral framework and the internal contractile components of the muscle fiber. In addition, the ability to sustain eccentric muscular contractions appears to be drastically reduced in individuals with DMD (which serves as an indication of muscle weakness) compared to controls.
  
- {{:​Dystrophin.png|}} ​+<style float-center>​ 
 + {{ :​Dystrophin.png |}} 
  
 //Figure 3 : Dystrophin, as well as Dystrophin-associated protein complexes (called Costamers), link cytoskeletal elements to the exoskeleton of the sarcolemma. In DMD, dystrophin is dysfunctional (or absent), leading to a disintegration of the internal framework of the muscle fiber.// //Figure 3 : Dystrophin, as well as Dystrophin-associated protein complexes (called Costamers), link cytoskeletal elements to the exoskeleton of the sarcolemma. In DMD, dystrophin is dysfunctional (or absent), leading to a disintegration of the internal framework of the muscle fiber.//
  
 +</​style>​
  
 **2. Calcium Hypothesis.** Deficiencies in dystrophin protein in the sarcolemma lead to an increased calcium influx, mostly through the mechanosensitive calcium channels. Normally, this increased influx triggers calcium homeostatic mechanisms in order to maintain normal calcium concentrations. However, if excessive mechanical stress (i.e. loss of muscle fiber structure, as discussed above) occurs, which induces microlesions in the fiber membrane, high influx of extracellular calcium inevitably overrides the capacity of the muscle fiber to maintain physiologic calcium homeostasis. This leads to the activation of proteases, resulting in further disintegration of membrane components, ultimately leading to cell necrosis. **2. Calcium Hypothesis.** Deficiencies in dystrophin protein in the sarcolemma lead to an increased calcium influx, mostly through the mechanosensitive calcium channels. Normally, this increased influx triggers calcium homeostatic mechanisms in order to maintain normal calcium concentrations. However, if excessive mechanical stress (i.e. loss of muscle fiber structure, as discussed above) occurs, which induces microlesions in the fiber membrane, high influx of extracellular calcium inevitably overrides the capacity of the muscle fiber to maintain physiologic calcium homeostasis. This leads to the activation of proteases, resulting in further disintegration of membrane components, ultimately leading to cell necrosis.
  
-{{:Calcium hypothesis.png}}+{{ :Calcium hypothesis.png }}
  
 //Figure 4: The calcium hypothesis of DMD// //Figure 4: The calcium hypothesis of DMD//
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 **3.Vascular hypothesis.** Earlier studies have proposed the possible role of abnormalities in muscular vasculature on the pathophysiology of DMD. However, structural studies have shown no such abnormalities. Rather, more recent insights into the local vasodilator role of nitric oxide and n-NOS in skeletal muscle may be more relevant to DMD. Nitric oxide is generated in skeletal muscle cells by the neuronal isoform of Nitric Oxide Synthase: n-NOS. In addition, n-NOS has an oxygenase domain, which plays a role in oxygen transport (i.e. oxidative phosphorylation). In muscles that have deficient dystrophin protein, n-NOS is delocalized from its subsarcolemmal anchorage, thus n-NOS floats freely in the cytoplasm, and its overall amounts in the sarcolemma is reduced. Therefore, during exercise conditions, when the need for oxygen transport in the sarcolemma is greatly increased, muscle ischemia may occur in DMD. The absence of sufficient n-NOS in the muscle fiber membrane also leads to reduced nitric oxide production, which causes vasoconstriction in the blood vessels, which further exacerbates the decrease in oxygen delivery to the muscle fibers. If prolonged oxygen deprivation is experienced,​ this eventually leads to increased susceptibility to metabolic stress, myofiber damage, and muscle fiber death. ​ **3.Vascular hypothesis.** Earlier studies have proposed the possible role of abnormalities in muscular vasculature on the pathophysiology of DMD. However, structural studies have shown no such abnormalities. Rather, more recent insights into the local vasodilator role of nitric oxide and n-NOS in skeletal muscle may be more relevant to DMD. Nitric oxide is generated in skeletal muscle cells by the neuronal isoform of Nitric Oxide Synthase: n-NOS. In addition, n-NOS has an oxygenase domain, which plays a role in oxygen transport (i.e. oxidative phosphorylation). In muscles that have deficient dystrophin protein, n-NOS is delocalized from its subsarcolemmal anchorage, thus n-NOS floats freely in the cytoplasm, and its overall amounts in the sarcolemma is reduced. Therefore, during exercise conditions, when the need for oxygen transport in the sarcolemma is greatly increased, muscle ischemia may occur in DMD. The absence of sufficient n-NOS in the muscle fiber membrane also leads to reduced nitric oxide production, which causes vasoconstriction in the blood vessels, which further exacerbates the decrease in oxygen delivery to the muscle fibers. If prolonged oxygen deprivation is experienced,​ this eventually leads to increased susceptibility to metabolic stress, myofiber damage, and muscle fiber death. ​
  
-{{:Vascular hypothesis.png}}+{{ :Vascular hypothesis.png }}
  
 //Figure 5: The vascular hypothesis of DMD// //Figure 5: The vascular hypothesis of DMD//
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 **4. Inflammatory Hypothesis.** Muscle biopsies of patients with DMD consistently demonstrate inflammatory response upregulation. In these individuals,​ there have been an observed coordinated activity of numerous components of a chronic inflammatory response, such as cytokine and chemokine signaling, leukocyte adhesion and diapedesis, invasive cell type-specific markers, and complement system activation. In particular, CD4+ or CD8+ T cells or macrophages have been shown to aggravate the symptoms of the disease. However, the exact relationship between the immune response and disintegration of the muscle fiber components is yet to be investigated. One proposed mechanism is that these inflammatory agents phagocytize the muscle fibers, leading to muscle wasting. Also, most studies have provided little direct evidence on the mechanisms of inflammatory functions implicated in muscle fiber death. **4. Inflammatory Hypothesis.** Muscle biopsies of patients with DMD consistently demonstrate inflammatory response upregulation. In these individuals,​ there have been an observed coordinated activity of numerous components of a chronic inflammatory response, such as cytokine and chemokine signaling, leukocyte adhesion and diapedesis, invasive cell type-specific markers, and complement system activation. In particular, CD4+ or CD8+ T cells or macrophages have been shown to aggravate the symptoms of the disease. However, the exact relationship between the immune response and disintegration of the muscle fiber components is yet to be investigated. One proposed mechanism is that these inflammatory agents phagocytize the muscle fibers, leading to muscle wasting. Also, most studies have provided little direct evidence on the mechanisms of inflammatory functions implicated in muscle fiber death.
  
-{{:​Inflammation.png}}+<style float-center>​ 
 +{{:​Inflammation.png|}}
  
 //Figure 6: The inflammatory hypothesis of DMD// //Figure 6: The inflammatory hypothesis of DMD//
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 ===== Curent Treatments ===== ===== Curent Treatments =====
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 In addition to these lifestyle recommendations,​ patients are encouraged to attend various therapies such as physical, respiratory,​ speech, and occupational therapy (NIH, 2016). In addition to these lifestyle recommendations,​ patients are encouraged to attend various therapies such as physical, respiratory,​ speech, and occupational therapy (NIH, 2016).
  
-===== Future Treatments =====+===== Future Treatments ​and Future Implications ​=====
  
 Though there are different targets available for potential treatment of DMD, these treatments only manage the symptoms but do not stop the progression of the disease (Young et al., 2016). Currently researchers are investigating how stem cells could be used to treat DMD in the future. Another growing field of research involves gene editing. Therefore, scientists are looking at combining both methods to treat DMD in the future. Dystrophin is the largest human gene, which causes implications in gene therapy (Young et al., 2016). Additionally,​ cell therapy has limitations because skeletal muscle is the most abundant in the human body (Young et al., 2016). Though there are different targets available for potential treatment of DMD, these treatments only manage the symptoms but do not stop the progression of the disease (Young et al., 2016). Currently researchers are investigating how stem cells could be used to treat DMD in the future. Another growing field of research involves gene editing. Therefore, scientists are looking at combining both methods to treat DMD in the future. Dystrophin is the largest human gene, which causes implications in gene therapy (Young et al., 2016). Additionally,​ cell therapy has limitations because skeletal muscle is the most abundant in the human body (Young et al., 2016).
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