Muscular dystrophy is an inherited disease where the different genes that control muscular function are defective (Emery, 2008). It has been found that many forms of dystrophy are caused by a deficiency in dystrophin, which is a muscle protein (Emery, 2008).
This disease is not infectious and cannot be acquired from any activity. It is characterized by muscle weakness and wasting where the specific muscles affected vary for different types of dystrophy (Emery, 2008).
Among the various types of muscular dystrophy, the Duchenne muscular dystrophy is the most prevalent, with an occurrence of twenty to thirty cases for every one thousand live male births (Brown, Miller & Eason, 2006). Another common type is the Becker muscular dystrophy, which is less severe than the Duchenne and occurs in three out of every one hundred thousand boys (Brown et al., 2006).
Normal Physiology
There are various types of muscles in the body, which can be either involuntary or voluntary and striated or smooth muscle fibers (Tompkins, 2010). It works with various chemical reactions in the body, as well as with the nervous system. The muscles are mainly made up of proteins and are organized into small fibers or big groups. Plasma membranes called sarcolemma are responsible for separating the muscle units from the other muscle groups. Within the sarcolemma is a cytoplasm referred to as the sarcoplasm, inside of which are the myofibrils or multiple long protein bundles. In addition, the sarcoplasm contains the myogoblin, glycogen, and the many mitochondria that produce ATP (adenosine triphosphate). As well, the myofibrils are made up of parallel myofilaments where contractile proteins referred to as actin and myosin are found. Actin consists of the thin filaments while myosin consists of the thick filaments.
Upon receiving a signal, the myosin and actin “interlock and slide over each other to stretch or slide into one another to contraction” (Tompkins, 2010, p. 2). They receive such signals from the nervous system, which are followed by a series of chemical reactions that involve the potassium and sodium ions, calcium, and ATP.
Other proteins that are involved in the movements of muscles include the regulatory muscles such as the troponin and the tropomyosin, which determine when the muscles should relax or contract. In addition, the I band can be found in the space between the myosin on the muscle fiber and the Z disc can be found at the center of each I band. The Z disc is composed of titan, “which is connected to the sarcolemma by the cytoskeleton” (Tompkins, 2010, p. 3). There is also a space between each Z disc, referred to as the sarcomere, where the interaction of the filaments takes place. The I band then shrinks when the muscle contracts, making the sarcomere shorter and the Z discs come closer together, in turn pulling the sarcolemma, which shortens the cell.
Dystrophin, an accessory protein, is also found in the area of the I band, particularly under the sarcolemma inside the cytoplasm. It connects the actin filaments and the dystrophin-associated protein complex, which is the protein extracellular matrix within the membrane. Although the real function of the dystrophin is still unknown, experts believe that it mainly serves as a mechanical reinforcement to the sarcolemma’s structure; thus, providing the membrane with protection from tearing or stress during muscle contraction (Tompkins, 2010).
Pathology of the Disorder
In muscular dystrophy, the dystrophin is either absent or defective. This causes the membrane to break down, in turn causing the leakage of substances and molecules such as enzymes and proteins from the fiber into blood circulation. However, it should be noted that these chemicals and enzymes that leak out are needed for producing specific types of chemical reactions and for producing the energy needed for muscle contraction. As well, the extracellular substances leak into the fiber through the torn membrane, which in turn damages the fiber and disrupts the muscle contraction process. It may even cause irreparable damage.
Without dystrophin, which protects and keeps the fiber membrane intact, as well as assists in the production of energy, the muscles would begin to degenerate and waste away. The dystrophin is replaced by fibrous scar tissue and fat, which results in fascia adhesions occurring in the entire body. According to Petrof et al. (Tompkins, 2010), the degree of membrane damage is determined not by the number of muscular activations but by the level of stress that result from the muscle contraction. With muscular dystrophy, the dystrophin genes limit or prevent the production of dystrophin at subnormal levels.
In general, small tears in the sarcolemma are a normal occurrence when the muscle is used in excessively strenuous activities. However, small molecules are present, which facilitate the repair process. On the other hand, though, the absence of the dystrophin leaves the sarcolemma with no protection; thus, making it more easily and frequently torn. Eventually, the regeneration of the muscles is unable to cope with its quick degeneration, which can then result in tissue adhesions and even death.
Prognosis
Duchenne muscular dystrophy occurs in boys aged from 4 to 6 years old. Muscular weakness begins somewhere around the pelvis and by the time that boy starts going to school, he is bound to start walking on the balls of his feet or on his toes (Brown et al, 2006). His belly may also jut out in an effort to maintain his balance while walking. As the disease progresses, weakness in the legs, trunk, arms, and shoulders develop. With the muscles continuing to weaken, they become larger but less functional. By adolescence, most of the boys with this condition are unable to walk and by their teens, their respiratory and heart muscles start to get affected. This condition usually causes death prior to the age of 20.
On the other hand, while the signs of Becker muscular dystrophy are similar to those of the Duchenne, they usually don’t manifest until the adolescence or early adulthood stage. As with Duchenne, the weakness starts at the pelvic and spreads to the shoulders, arms and thighs. The disease progresses at various rates for different people where some men become wheelchair-bound by the age of 30 while others manage to keep walking with the use of canes for many years. 90 percent of those with the Becker muscular dystrophy often survive beyond the age of 20 (Brown, et al., 2006).
Treatment
There is presently no cure for muscular dystrophy. Gene therapy is the only real cure where the defective gene is replaced by a normal gene (Emery, 2008). However, this form of treatment is still being developed and its development is made even more complicated by the fact that the defective gene is active in the brain as well as in every “muscle cell of the body” (Emery, 2008, p. 42). Moreover, it can also be present in other organs or tissues of the body, depending on the type of dystrophy.
However, despite the lack of cure, some steps can be taken to relieve the problems that come with muscular dystrophy and to somehow improve the quality of the patient’s life in general. These include the “promotion and maintenance of good health in general;” the “prevention of deformities through exercises, physiotherapy, orthoses, and surgery;” and the “preservation of respiratory function” (Emery, 2008, p. 42).
The patient’s health can be maintained through a well-balanced diet that is rich in fiber and that includes fresh fruits and vegetables (Emery, 2008). The patient should also be kept from becoming overweight. In addition, physical therapy and exercise can help keep the patient’s muscles strong and flexible (Walton, 2010).
As well, the patient can be massaged in order to “prevent disabling contractures” (Walton, 2010, p. 116). Moreover, assistive devices such as wheelchairs, walkers, and braces can be used to enable the patient to easily move around. Similarly, assisted ventilation can be employed to assist the patient with his breathing. In particular, this can be started at night and expanded during the day when the breathing problems progress.
Surgery may also be performed on patients with severe muscle contractions (Walton, 2010). Moreover, Corticosteroid medication (e.g. prednisone) may be administered as this medicine has been shown to help maintain the patient’s strength and prolong their ability for walking. However, this medicine is usually used only in severe cases due to the side effects that come with its prolonged use (Walton, 2010).
Clinical Trials
In 2011, researchers at Chapel Hill’s North Carolina University have found that it is safe to cut and paste different viruses together in order create a virus that will be an ideal vehicle for gene therapy (Bowles, McPhee, Li & Gray et al., 2012). The study showed that no side effects resulted from the use of a chimeric virus in delivering replacement genes for the defective genes that cause muscular dystrophy. This study also showed that the administration of gene therapy for muscular dystrophy treatment does not have to be limited to the use of viruses that are found in nature. Moreover, although there are many safe viruses that are available in natural settings, none of them are perfect for use in gene therapy.
In a study conducted by Anthony, Cirak, Torelli & Tasca et al. (2011), all of the internally deleted dystrophin that were tested in the study were functionally capable of providing significant clinical benefit to patients who suffer from Duchenne muscular dystrophy. This implied that exxon skipping with the use of antisense oligonucleotides that are targeted to splicing elements can be performed to restore the open frame that prevents the production of dystrophin. With this approach, the phenotype for Duchenne muscular dystrophy is transformed into that of Becker muscular dystrophy, which is a milder condition that is “caused by in-frame dystrophin deletions that allow the production of an internally deleted but partially functional dystrophin” (Anthony et al., 2011, p. 3547). As such, the findings of Anthony et al. (2011) helped shed some light on debates regarding the functionality of various internally deleted dystrophins that are generated by performing exxon skipping on various types of mutations.
Furthermore, a study conducted by Brzoska, Kowalewska, Markowska & Kowalski et al. (2012) “showed that stromal derived factor- 1 (Sdf-1) impacts at the mobilization of Cxcr4-positive cells and improves skeletal muscle regeneration.” This is based on the premise that satellite cells are involved in the process of regenerating the skeletal muscles, which may have been damaged either by an injury or a disease such as muscular dystrophy. When the muscles start to regenerate, cytokines and growth factors are released locally, which causes the satellite cells to be activated and proliferated and for the resulting myoblasts to be differentiated. This in turn results in the creation of new myofibers. Moreover, other types of cells, such as the progenitor and stem cells, originate from tissues other than the muscle and can also follow the myogenic process. I this regard, the role that these cells play in the regeneration process “depends on their mobilization to the site of the injury” (Kowalewska, Markowska & Kowalski et al., 2012).
In the analysis of in vitro cultured and isolated satellite cells that was performed by the researchers, it was found that Sdf-1 had no influence over the proliferation of the myoblasts nor on the expression of MRFs (myogenic regulatory factors) (, Kowalewska, Markowska & Kowalski et al., 2012). However, the analysis did show that Sdf-1 led to the “migration of the myoblasts in Cxcr4 dependent way” (Kowalewska, Markowska & Kowalski et al., 2012). Moreover, this led to an increase in the activity of the crucial extracellular matrix modifiers, particularly the metalloproteases Mmp-9 and Mmp-2 (Kowalewska, Markowska & Kowalski et al., 2012). This study concluded that a relation existed between the mobilization of the endogenous cells – which include the myoblasts, satellite cells, and the non-muscle stem cells that express CD34 and Cxcr4 – and the positive impact that Sdf-1 had on muscle regeneration (Kowalewska, Markowska & Kowalski et al., 2012).
References
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Sdf-1 (CXCL12) improves skeletal muscle regeneration via the mobilization of Cxcr4
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from http://onlinelibrary.wiley.com/doi/10.1111/boc.201200022/abstract
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Walton, T. (2010). Medical conditions and massage therapy: A decision tree approach.
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