The Effect Of Insufficient Production Of Dystrophin

2. The typical microscopic changes noted in the muscle tissue of someone with Duchenne’s muscular dystrophy is degenerating skeletal muscle cells. Surrounding these muscle cells is a large amount of endomysial connective tissue that is proliferating. A large number of macrophages can be seen whose responsibility is to eliminate cellular debris. Some muscle cells (fibers)

Muscle atrophy is the loss of skeletal muscle mass and function that occurs when there is a long period of inactivity of the muscles or defects in motor neuron's (Reilly, Beau 2015). Defects in the motor neurons that stimulate the muscle cause the muscle mass to decrease as proteins that initiate contractions of muscle dissipate. Stimulus is not transferred to the weakened muscle fibers effectively, reducing the contractile force possible for generation from the stimulus. Muscle mass increases upon recovery, as restimulation of the muscle enlarges fiber size, thus a greater contractile force can be generated from the stimulus.

Duchenne Muscular Dystrophy is a disease which causes skeletal muscle to waste away, this wasting of muscle is caused by a mutation of the dystrophin gene (Meregalli et al., 2013, p. 4251).

Actin and myosin filaments can be found in skeletal muscle and are the smallest units that form a sarcomere, which is the smallest contractile unit in muscle (Baechle, 2008). The Sliding Filament Theory states that the actin filaments slide inward on the myosin filaments, pulling on the boundaries of the sarcomere, causing it to shorten the muscle fiber, also known as a concentric muscular contraction (Baechle, 2008). The Sliding Filament Theory is composed of five steps: the “Resting Phase”, the “Excitation-Contraction Coupling Phase”, the “Contraction Phase”, the “Recharge Phase”, and the “Relaxation Phase” (Baechle, 2008). During the Resting Phase, the actin and myosin filaments are lined up with no cross-bridge binding of the two filaments. During the Excitation-Contraction Coupling Phase, Calcium is released from the sarcoplasmic reticulum and binds to troponin, causing a shift in tropomyosin where the binding cites are exposed (Baechle, 2008). When the binding cites are exposed, the myosin cross-bridge head attaches to actin. During the Contraction Phase, ATP bonds break, releasing energy that is used to allow the myosin head to flex, causing the actin filaments to move toward the M-bridge. During the Recharge Phase, there is a continuous repetition of the Excitation-Contraction Coupling Phase and the Contraction Phase in order to produce muscular

Duchenne muscular dystrophy was first discovered by Guillaume Benjamin Amand Duchenne in the 1860’s, but due to lack of medical knowledge little was known until the 1980’s. It was in 1986 that researchers that were supported by the MDA, muscular dystrophy association, identified the particular X-chromosome that leads to DMD, Duchenne muscular dystrophy. Dystrophin is the protein that is associated with the gene and was named in 1987.The DMD gene is the second largest gene to date, and it produces dystrophin.(Genome, 2013) Lack of the protein Dystrophin in the muscle cells causes them to weaken and become fragile. (MDA, 2015). DMD is an inherited disorder, but there are rare cases where it can spontaneously appear in a child with no previous family history due to a random mutation in moms X-chromosome. DMD is a gender specific disease that only appears in males.

When a cell becomes damaged and undergoes apoptosis the muscle cells may not be able to regenerate at a proper rate to avoid a deficiency in the amount of the nuclei needed to maintain proper muscle mass. Support for this need and the suggestion that nuclei number may be size limiting and therefore a causation for atrophy was found in the study by the observation of damaged myonuclei were found in stage 3 mice but absent in stage 1, myonuclei reduction in the two muscle samples, nuclear domain size in regards to surface area was either maintained or increased, and the reappearance of a correlation between nuclei number and fiber size in stage 3 muscles. Particularly EDL IIb fibers may be most susceptible to sarcoma due to a generally lower nuclei number and that distribution of these fibers is impaired in the elderly which would not reduce capacity for synthesis but could increase transport distances causing decreased functionality. The nuclear shape also changed which has an unknown impact on functionality and may have been the cause of the nuclear fragmentation possibly leading to

DMD is caused by a mutation in the X-linked dystrophin gene, which results in a dysfunctional dystrophin protein. Dystrophin is a cytoskeletal protein that provides mechanical stability to muscle cells by connecting the muscle sarcolemma to the basal lamina of the extracellular matrix (ECM), and without it there, the muscle cells typically undergo a process of degeneration and regeneration. This process is limited by the survival of satellite cells present since satellite cells can only undergo mitosis a limited amount of times. Sarcolemma instability typically results in excess intracellular amounts of both sodium and calcium, which causes ATP depletion and mitochondrial uncoupling (Horn & Schleip, 2012). Satellite cells only have a limited number times they can undergo mitosis, and once a patient can no longer generate healthy muscle cells, the patient will typically experience cell death. This cell death and necrosis usually

Duchenne Muscular Dystrophy (DMD) is a fatal genetic disorder that is caused by mutations in the gene DMD, which encodes the muscle protein, dystrophin. Dystrophin protein is crucial to preserve the strength, stability, and flexibility of muscle fibers, which protects them from injury as they contract and relax. The DMD gene is primarily located in skeletal and cardiac muscle. Duchenne Muscular Dystrophy is caused by mutations in the gene that produce premature stop codons. The premature stop codons work to bring protein synthesis to a halt, resulting in a greatly shortened and nonfunctional form of dystrophin (Pierce, 2013, pg. 286). According to the Muscular Dystrophy Association (2016), “Individuals with DMD experience rapid progressive

Muscles owe their ability to contract to structural units called sarcomeres, and a single muscle fiber can contain many thousands of these structures, aligned one next to the other. Each mature sarcomere is made up of precisely arranged and intertwined thin filaments of actin and thicker bundles of motor proteins, surrounded by other proteins. Sliding the motors along the filaments provides the force needed to contract the muscle. However, it was far from clear how sarcomeres, especially the arrays of thin-filaments, are assembled from scratch in developing muscles.

Pasternak C, Wong S, Elson EL. (1995). Mechanical function of dystrophin in muscle cells. The Journal of Cell Biology, 128(3), 355-361. doi:10.1083/jcb.128.3.355

Desmin is a type III intermediate filament protein that is muscle-specific and is found in all muscle types: smooth, cardiac, and skeletal. Autosomal dominant and autosomal recessive desmin gene mutations affect desmin (DES) and oftentimes αβ-crystallin (CRYAB), a chaperone for DES, which leads to a type myofibrillar myopathy, known as desminopathy (Goldfarb et al., 2010). Desmin is the most abundant IF protein in striated and smooth muscle cells and is one of the earliest markers of muscle development (Clemen et al., 2012). Desmin filaments are mainly located at the periphery of Z-disk of striated muscles and at the dense bodies of smooth muscle cells, and they have been thought to play a major role in the maintenance of structural and mechanical integrity of the contractile apparatus in muscle tissues (Paulin & Li, 2004). A dysfunctional desmin protein cannot properly interact with Z-discs, leading to abnormalities of sarcomere structure and problems with the formation of myofibrils (NIH, 2016). The resulting pathology, desminopathy, is one of the most common intermediate filament human disorders associated with mutations in closely interacting proteins (Goldfarb & Dalakas, 2009). This condition is defined as skeletal and cardiac myopathy characterized by the presence of chimeric aggregates in muscle fiber areas that consist of DES, CRYAB and other proteins (Goldfarb et al., 2010). While a few desmin-related

Muscular dystrophy (MD) is a genetic disorder caused by incorrect or missing genetic information that leads to the gradual weakening of the muscle cells. Various causes lead to weak and deteriorating muscles depending on the type of muscular dystrophy the patient was affected by. However, there are many causes for muscular dystrophy due to the fact that there are thirty forms of muscular dystrophy, which are categorized under several categories. All are ultimately caused by autosomal recessive, autosomal dominant, sex-linked, and random mutations in very rare cases.

The Duchenne muscular dystrophy gene causes deletions of nucleotides which interrupts the translational reading frame. What could help restore the reading frame is by eliminating additional exons around the inherited deletion. The target exon for this restoration to happen is exon 51. Another treatment that could positively affect a patient with this disorder is using genome editing by creating a targeted frameshift. For this treatment to be effective nucleases are directed to sites within exons around the deleted region of the gene will insert a small indel that restores the translational reading frame (Hamm & Gersbach, 2016). Also, meganucleasese are used to insert small indels that will restore the reading frame of a modified Duchenne muscular dystrophy gene. This treatment is successful, majority of the time, however, if too many small indels are inserted into gene or not enough indels are inserted into the gene it could cause point mutation (Hamm & Gersbach, 2016). A point mutation could lead to missense mutation, nonsense mutation, neutral mutation, silent mutation, or frameshift mutation. The last treatment that could be used to help patients affected by this disorder is homologous recombination. This treatment does not have the same effect has the treatments above and it also downregulated in post-mitotic cells such as muscle fibers. Genome editing of the Duchenne muscular dystrophy gene has been successful in

Muscular dystrophy (MD) is a rare, progressive disease relating to the weakening of skeletal muscles. There are more than 30 types of muscular dystrophy that are further divided into nine categories. Duchenne MD is the most common and acute form of this condition that accounts for 50% of all the cases. Duchenne MD (DMD) is most prevalent in males, between the ages of 3 and 5 (Norwood, FL, et al. 2009). This X-linked disease occurs for 1 in every 3,500 males, which results in confinement to a wheelchair (Blake et al., 2002). Becker MD (BMD) is a less severe type of this condition. A study conducted in the United Kingdom by Bushby, Thambyayah and Gardner-Medwin, the incidence of Becker MD was estimated to be 1 in 18,450 males at birth

Muscle Fibre Tear- When the muscles contract they create micro tears within the muscle and require protein in order to mend the muscles. These tears are repaired into stronger and denser fibres. For example if an individual went on the treadmill for 10 minutes, the hamstrings,