Description of Pathology
Muscular dystrophy involves more than thirty genetic disorders that cause loss of muscle mass and progressive weakness. The proteins involved in the production of healthy muscles used in the voluntary movement are interfered with by mutations or abnormal genes. The disease presents itself in many symptoms from childhood, especially in boys; however, some types are asymptomatic until adulthood. Muscular dystrophy has no cure, even though therapy and medication help in slowing the course of the disease and managing its symptoms. In several instances, muscular dystrophy runs in families where it develops in case a faulty gene is inherited from one or both parents. It is estimated that globally, in 100,000 people, around 3.6 people have muscular dystrophy (Salari et al., 2022). The Americans have the largest prevalence, with 7.8 per 100,000 individuals. Additionally, in many cases, most people end up losing the ability to walk due to muscle degeneration.
For example, Duchenne muscular dystrophy is one form of disease that is caused by a genetic mutation of one of the X chromosomes in the mother. This form results from a genetic problem in producing dystrophin protein (Markati et al., 2022). When muscle fibres are exposed to enzymes, dystrophin protects them from breaking down. This type of muscular dystrophy worsens quickly compared to other forms like Becker muscular dystrophy. Around 20,000 children are estimated to be diagnosed with Duchenne each year, while in 5,000, like male birth, one is estimated to have the disease.
Normal anatomy of the major body system affected
Muscular dystrophy mainly affects the skeletal muscles. Connective tissue sheaths wrap together the thousands of muscle fibres that make a single skeletal muscle. The muscle fibres form individual bundles in the skeletal muscle called a fasciculus. The epimysium surrounds the entire muscle and is the outermost connective tissue sheath. The perimysium is the connective tissue sheath that surrounds an individual fasciculus. A single muscle fibre has several myofibrils, which have multiple myofilaments. When all the myofibrils are arranged in a specific pattern that is straited, they form sarcomeres. Sarcomeres are the ultimate contractile component in the skeletal muscle. The myosin and the actin filaments are the most important myofilaments, which are arranged characteristically to form specific bands on the skeletal muscle. Satellite cells are the stem cells that differentiate into mature muscle fibres. They are found between the sarcolemma and the basement membrane. Additionally, they are stimulated by growth factors to form new muscle fibre cells after differentiation.
The major skeletal muscle function occurs through its intrinsic excitation-contraction coupling process. Muscle contraction causes movement of the bone since it is attached to the tendons, thus allowing the performance of specific movements. The muscles also help maintain body posture and provide structural support. They also act as a storage source for amino acids, play a role in thermostatic maintenance and provide energy during starvation.
Normal physiology of the major body system is affected.
Motoneurons are accountable for innervating the muscle fibres. The innervated muscle fibre and the single motor neuron form a motor unit. The contraction of the skeletal muscles starts at the neuromuscular junction, the synapse between the muscle fibre and the motoneuron. The opening of the calcium (Ca2+) voltage-gated channels at the presynaptic membrane is caused by action potential propagation to the motoneuron followed by depolarization. When (Ca2+) flows inwards, it causes the neuromuscular junction to produce acetylcholine (ACh) which later diffuses at the muscle fibre’s postsynaptic membrane (motor endplate). At the motor endplate, ACh bind to nicotinic receptors causing depolarization and initiating action potentials (AP). The excitation-contraction coupling allows the conversion of action potentials in the muscle fibres into contractions. The AP at the myofibrils cell membrane travel to the T tubule. Dihydropyridine receptors are contained in the T- tubules. These receptors go through conformational change after depolarization of the T- tubules causing mechanical interaction with ryanodine receptors which are located on the sarcoplasmic reticulum. Ca2+ are released from the sarcoplasmic reticulum after the ryanodine receptors open as a result of the interaction. The intracellular Ca2+ bind to troponin C causing cooperativity. As a result, there is a conformational change of the troponin complex, causing tropomyosin displacements from the myosin binding site, therefore, binding of the myosin thick filaments.
The cross-bridge cycle that happens before excitation-contraction coupling produces a muscle contraction. Here, the myosin head progresses up the actin filament when Ca2+ is only bound to troponin C. After the release of the ADP; myosin goes back to its normal state (rigour). At this stage, it is bound to actin in ATP adenosine triphosphate absence.
Muscle contraction is followed by its relaxation. This occurs when there is reaccumulation of Ca2+ in the sarcoplasmic reticulum. The active Ca2+ ATPase (SERCA) pump allows the transportation of Ca2+, allowing the maintenance of low Ca2+, and thus the muscle is relaxed. Decreased levels of intracellular Ca2+ cause Ca2+ to dissociate from troponin C which is followed by blockage of myosin binding sites by tropomyosin on the F actin.
Mechanism of pathophysiology
The mechanism of this pathology occurs through increased Ca2+, which leads to muscle wasting. Calpains are calcium-dependent proteases which are activated in muscular dystrophy, eventually leading to muscle protein degradation and necrosis. Calcium chelators or protease inhibitors inhibit the activity of calpain in dystrophic myofibers. Ameliorate dystrophinopathy results from calpain inhibition. Ca2+ are vital secondary messengers which induce specific responses intracellularly. For instance, activation of specific signalling pathways and excitation-contraction coupling. Thus, the activation of specific signalling pathways and the excitation-contraction coupling can be adversely affected by abnormal Ca2+ homeostasis. Via stretch-activated channels, mechanical stretch can increase the influx in Ca2+, leading to the activation of signal-regulated kinase 1 /2 that occurs extracellularly and the activation of downstream proinflammatory transcription factors. For example, in the myofibers, there is activator protein -1 (AP1). The abnormal activation of extracellular signal-regulated kinase1/2 (ERK) via the elevated influx of Ca2+ is also seen in muscular dystrophy. A report by Meng et al. shows that in cultured mdx mice myotubes, the resting Ca2+ is higher, and it has a great contribution to the activation of transcription factor – proinflammatory nuclear factor-kappa B (NF-κB) in addition to the inducible nitric oxide synthase (iNOS) which is a downstream target gene.
Increased levels of calcium ions also modulate calcineurin activity via the nuclear factor of the activated T-cells (NFAT) pathway, thus causing muscle pathology. Calcium- and calmodulin-dependent phosphatase calcineurin dephosphorylates NFAT as a result of increased levels of intracellular calcium, therefore, causing the transcription factor to be nuclear translocate (Dong et al., 2022). Interestingly calcineurin transgenic expression in the skeletal muscle led to elevated NFATc1 nuclear localization, better sarcolemmal integrity, increased utrophin levels and slower phenotype fibre type shifting. In mdx slow dystrophic phenotype, the type fibres exacerbate repressing utrophin levels due to overexpression of the calmodulin small peptide inhibitor. Consequently, the serum levels of calcineurin go down in patients accounting for the impairment of the regeneration of muscles and, thus, severe pathology in muscular dystrophic patients.
Prevention
Muscular dystrophy can not be prevented. However, some steps may help an individual with the disease live a quality life. For example, eating healthy, hydrating, exercising often, maintaining a healthy weight, getting pneumonia and flu vaccines and quitting smoking with the aim of protecting the heart and the lungs.
Treatment
Muscular dystrophy can be treated by physical therapy, which involves stretching exercises and physical activities. Respiratory therapy; since our bodies rely on diaphragm muscles to breathe and the disease may affect breathing. Speech therapy; helps maximize muscle strength. Surgery; helps individuals with myotonic muscular dystrophy by installing pacemakers to treat heart problems. Some may require curvature of the spine or scoliosis. Drug therapy; delays muscle damage reducing its symptoms. For example, glucocorticoids (deflazacort or prednisone), immunosuppressants, beta blockers and anticonvulsants. Gene-based therapy; this method restores the gene’s ability to synthesize proteins needed for the treatment of muscular dystrophy. However, this is an area under research though it is very promising. Gene therapy can also fall under exon skipping, where drugs like eteplirsen are used to produce unstable dystrophin protein skipping the muscle problem-related gene (Eser & Topaloğlu, 2022)
Conclusion
Muscular dystrophy involves genetic disorders that cause loss of muscle mass and progressive weakness. The proteins involved in the production of healthy muscles are interfered with by mutations. The normal physiology of the skeletal muscles is aided by the motoneurons, which are accountable for innervating the muscle fibres. The excitation-contraction coupling allows the conversion of action potentials in the muscle fibres into contractions. Relaxation of the skeletal muscles is activated by the active Ca2+ ATPase (SERCA) pump that allows transportation of Ca2+, allowing the maintenance of low Ca2+ and thus relaxing the muscle.
The regulation of the calcium (Ca2+) voltage-gated channels determines the relaxation and contraction of these muscles. However, increased levels of calcium ions lead to muscle wasting. The calcium-dependent proteases (calpains) are activated in muscular dystrophy, eventually leading to muscle protein degradation and necrosis, thus, muscular dystrophy. Additionally, increased levels of calcium ions also modulate calcineurin activity via the nuclear factor of the activated T-cells (NFAT) pathway, thus causing muscle pathology. This disease cannot be prevented as it arises in case a faulty gene is inherited from one or both parents. However, some steps like eating healthy, hydrating, exercising often, maintaining a healthy weight, getting pneumonia and flu vaccines and quitting smoking can help a patient live a quality life. Lastly, several treatment methods have been used to keep its symptoms under control. For example, the use of gene-based therapy, respiratory therapy, speech therapy, physical therapy and drug therapy. All these forms of therapy help keep the muscle strength maximized therefore controlling the disease.
References
Dong, X., Kong, L., Huang, L., Su, Y., Li, X., Yang, L., … & Li, W. (2022). Ginsenoside Rg1 treatment protects against cognitive dysfunction via inhibiting PLC–CN–NFAT1 signaling in T2DM mice. Journal of Ginseng Research.
Eser, G., & Topaloğlu, H. (2022). Current outline of exon skipping trials in Duchenne muscular dystrophy. Genes, 13(7), 1241.
Markati, T., Oskoui, M., Farrar, M. A., Duong, T., Goemans, N., & Servais, L. (2022). Emerging therapies for Duchenne muscular dystrophy. The Lancet Neurology.
Meng, F., Guo, B., Ma, Y. Q., Li, K. W., & Niu, F. J. (2022). Puerarin: A review of its mechanisms of action and clinical studies in ophthalmology. Phytomedicine, 154465.
Salari, N., Fatahi, B., Valipour, E., Kazeminia, M., Fatahian, R., Kiaei, A., … & Mohammadi, M. (2022). Global prevalence of Duchenne and Becker muscular dystrophy: A systematic review and meta-analysis. Journal of orthopaedic surgery and research, 17(1), 1-12.
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