Dystrophy Muscle Disease

Dystrophy Muscle disease describes a group of neuromuscular disorders which cause progressive wasting and weakening of skeletal muscle tissue (Emery, Muntoni, & Quinlivan, 2015). The condition is characterized according to the degree of muscle weakness, the muscles affected, and the onset of symptoms. There are different types of dystrophy muscle disease, which include, but not limited to, Duchenne, Becker, Limb-girdle, congenital, and FSHD muscular dystrophies. Muscular dystrophy is an X-linked disorder; thus, it is more prevalent in males than females. The disease is typically inherited as an X-linked recessive or at times dominant disorder that interferes with dystrophin production. In other cases, random gene mutations during early child development that cause errors in DNA replication or spontaneous lesions may also interfere with dystrophin production. Usually, dystrophin protein acts a shock absorber for mechanical stabilization and link between the sarcolemma and actin protein in the cytoskeleton. Mutations in the dystrophin gene on the X-chromosome in males may cause errors in translation or expression of dystrophin protein. “Lack of dystrophin in muscles results in progressive degeneration of muscles” (Emery, 2015). 

Electromyography, high concentration of creatine phosphokinase (CPK3), and muscle biopsy results and genetic testing are primary diagnostic procedures for dystrophy muscle disease. However, additional tests such as CT scan, MRI (magnetic resonance image) scan, chest cavity x-rays, and echocardiogram should be used to produce detailed images which assist physicians in diagnosing dystrophy muscle disease, as suggested by Emery et al. (2015). The condition has no cure although corrective surgery, use of braces, and physiotherapy can be used to alleviate primary symptoms of the disease. Moreover, corticosteroids and immunosuppressants can also be administered to delay the process of muscle degeneration. In cases where breathing muscles are affected, assisted ventilation can be used to help the affected individual(s) to breathe. This term paper will focus on physiological and metabolic effects of dystrophy muscle disease as well as available options for treatment from the basic cellular level to the complex organismal level. Some metabolic effects of muscular dystrophy include increased creatine phosphokinase concentration in the interstitial fluid, increased laminin, accumulation of fibrofatty infiltrates in muscles, as well as low cortisol concentration in the body. Physiological effects, on the other hand, include dysphagia, difficulty in breathing, urinary hesitancy, poor muscle coordination, loss of balance, and reduced cognitive development among young children. Moreover; subsequent sections will highlight the most common side effects of the treatment. 

Metabolic Effects 

In his book, Muscular dystrophies , Emery (2015) noted: “Interference in dystrophin protein synthesis prevents linkage between dystroglycan and actin proteins in myoblasts; thus inhibiting the fusion of myoblasts from forming skeletal muscle tissue fibers. The unfused myoblasts dedifferentiate into myosatellite cells which remain at the base of the endomysium sarcolemma. As a result, skeletal muscles undergo atrophy and lose their tone.” Typically, at muscle costomeres, dystrophin accumulates and forms links with dystrophin-associated glycoproteins (DAGs) at their C-terminus and with actin proteins at the N-terminus forming a dystrophin-glycogen complex which associates with laminin, as suggested by Emery (2015). However, dystrophy muscle disease inhibits the production of dystrophin protein, thus causing accumulation of dissociated laminin in the extracellular matrix. Increased levels of laminin in the extracellular matrix cause instability of myoblasts and increased leakage of cellular components, which results in a subsequent increase in creatine phosphokinase (CPK3) concentration. Elevated levels of CPK in the interstitial fluid causes activation of cytotoxic T cells, which cause massive destruction of damaged myoblasts. Fibrofatty infiltrates then replace the aggregative of dead myoblasts causing pseudohypertrophy in muscle tissue. Extensive myoblast necrosis causes progressive muscle weakness and contractures. 

Physiological Effects

Dystrophy of muscles may also cause breathing problems if the intercostal muscles or the diaphragm undergo dystrophy. The diaphragm also assists in urination and propulsion of vomit during gastric refluxes. The weakness of the diaphragm causes urinary hesitancy, which may lead to bladder irritation and subsequent development of bladder cysts. Furthermore, dystrophy of facial and cervical muscles may cause dysphagia (difficulty in swallowing), according to Emery (2015). Obicularis Oris and buccinators muscles are parts of musculature “sling’ which propagate food boluses towards the esophagus during swallowing. Dystrophy of either muscle may prevent the creation of positive pressure necessary for food propulsion, thus causing swallowing difficulties. The weakness of stylopharyngeus, salpingopharyngeus, inferior pharyngeal, and middle pharyngeal constrictor may inhibit bolus transport along the proximal section of the esophagus, thus causing dysphagia, according to King et al. (2017). In severe cases, dystrophy may extend to cardiac muscles and cause heart problems. Moreover, the disease may lead to shortening of tendons, which may interfere with a person’s joint movement and overall mobility. In isolated cases such as congenital muscular dystrophy, hydrocephalus or lissencephaly may develop in a developing infant, which might lead to cognitive developmental problems. 

Treatment and Side Effects

Treatment options available for dystrophy muscle disease may aim at treating either the cause or symptoms. Muscular dystrophy associated with dystrophin deficiency can be treated through gene therapy, which involves the insertion of a fully functional dystrophin gene on the X-chromosome using spice-switching oligomers as suggested by Nelson et al. (2016). Treating the symptoms involves administration of Lamin-111, which reduces the degradation cycles of muscles by increasing muscle resistance. Lamin-111 binds to laminin in the extracellular matrix to prevent laminin accumulation; thus, preventing leakage of intracellular components from myoblasts. Lamin-111 action helps to deactivate cytotoxic T cells by reducing the concentration of creatine phosphokinase in the interstitial fluid. Therefore, the overall rate of myoblast necrosis is reduced, thus inhibiting progressive muscle tissue degeneration. Steroids have also proven to improve muscle growth and strength (Emery, 2015). Corticosteroids increase muscle tissue metabolism by increasing protein catabolism, which causes an increase in muscle mass. 

Prolonged use of steroids such as corticosteroid medication causes muscle inflammation and joint pain, as suggested by King et al. (2017). In most cases, corticosteroids cause excessive growth of hair, weight gain, and low libido among males. However, in some isolated cases, corticosteroids interfere with bone formation, causing the development of osteoporosis. According to King et al. (2017), corticosteroids counteracts insulin, thus causing hyperglycemia and decreased GLUT4 translocation across the plasma membrane. 

Conclusion

There is ongoing research on the effectiveness of stem cells in the treatment of dystrophy muscle disease. Researchers are focusing on whether mesenchymal cells can be transformed into myoblasts and used to regenerate muscle fibers and tissues. According to Engvall and Wewer (2018), geneticists in liaison with other researchers are conducting trials in the UK and Netherlands to test the efficiency of exon skipping in treating Duchenne muscular dystrophy. Furthermore, the Muscular Dystrophy Association has funded research into a less invasive method of creatine phosphokinase concentration testing to diagnose the muscular dystrophy. Moreover, there are ongoing clinical trials on dystrophin protein dosage compensation to ascertain the effectiveness of the dosage compensation in alleviating the symptoms of dystrophy muscle disease among children. 

References

Emery, A. E., Muntoni, F., & Quinlivan, R. C. (2015). Duchenne muscular dystrophy . OUP Oxford.

Emery, A. E. (2015). The muscular dystrophies. The Lancet , 359 (9307), 687-695.

King, W. M., Ruttencutter, R., Nagaraja, H. N., Matkovic, V., Landoll, J., Hoyle, C., ... & Kissel, J. T. (2017). Orthopedic outcomes of long-term daily corticosteroid treatment in Duchenne muscular dystrophy. Neurology , 68 (19), 1607-1613

Nelson, C. E., Hakim, C. H., Ousterout, D. G., Thakore, P. I., Moreb, E. A., Rivera, R. M. C., ... & Asokan, A. (2016). In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science , 351 (6271), 403-407.

Engvall, E., & Wewer, U. M. (2018). The new frontier in muscular dystrophy research: booster genes. The FASEB Journal , 17 (12), 1579-1584.