Duchenne Muscular Dystrophy: A Detailed Pharmacology Overview

This report provides a detailed overview of Duchenne Muscular Dystrophy (DMD), a genetic disorder primarily affecting males, characterized by the absence of the dystrophin protein in muscle fibers. The report describes the condition's progressive nature, its impact on cardiac and skeletal muscles, and the typical symptoms observed in affected individuals. It explains how mutations in the DMD gene lead to inadequate dystrophin production, weakening muscle fibers and causing atrophy. The report also delves into the mechanisms by which the reduction or absence of dystrophin leads to clinical symptoms such as muscle weakness, reduced stiffness, and impaired cell signaling. Furthermore, the report references studies that support the calcium and mechanical hypotheses, explaining how dystrophin deficiency affects calcium ion regulation, membrane permeability, and the overall stability of muscle fibers. While there is no known cure, the report highlights available treatments for managing the symptoms of DMD.

Running head: PHARMACOLOGY
Pharmacology Assignment:
Duchenne Muscular Dystrophy
Name of the Student
Name of the University
Author Note

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Duchenne Muscular Dystrophy
Introduction:
Muscular dystrophy is a group of diseases that leads to degeneration, loss and
weakness of the muscles and muscle mass and is mainly caused due to genetic causes.
Duchenne Muscular Dystrophy (DMD) is a specific type of muscular dystrophy that occurs
predominantly among male. This is a genetic disorder that leads to an absence of the
cytoplasmic protein called dystrophin in muscle fibers thereby leading to the clinical
outcomes typical to the disease (Long et al. 2016; Li et al. 2015).
Description of the condition:
DMD is a progressive type of muscular dystrophy that is mainly diagnosed among
male, however females can also be affected in rare cases. The disease can occur at all ages,
however the symptoms becomes the most noticeable by the age of four. The disease leads to
the atrophy, loss and weakness of the cardiac and skeletal muscles thereby affecting their
function (Emery et al. 2015). The early symptoms of the disease can include a slower
movements while walking, sitting or standing or difficulties in speech. The atrophy and
muscular weakness usually starts with the musculature associated with the pelvis, hips,
shoulders and upper legs and can also cause an enlargement of the calves. Children afflicted
with this condition may show difficulties or abnormal gait while walking, running, climbing
stairs and while sitting down and getting up (Yiu and Kornberg 2015). The condition can also
impact memory and the ability of communicate. With progression of age, the condition
spreads to the trunk, arms and legs and a wheelchair is usually needed for movement.
Weakness of the muscle also leads to the cardiac and respiratory conditions (Angelini 2018).

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The condition is caused due to mutations in the DMD gene which codes for a specific
protein known as dystrophin (Ousterout et al. 2015). This is a cytoplasmic protein (present in
muscle fiber cells) which forms a protein complex (called the dystrophin associated protein
complex) that functions in the interconnection of the cytoskeleton of the cell to the
extracellular matrix. This allows dystrophin to maintain the strength of the muscle fibers
(Aartsma-Rus et al. 2016). The mutation of the DMD gene leads to the production of
inadequate amount of dystrophin leading to the atrophy of the muscle fibers. The gene is
linked to the X chromosome and is a recessive gene and therefore is usually inherited from a
family member. However the DMD can also occur spontaneously, without any family history
of the disease. The disease does not have any known cure, however treatments are available
that can be used to manage the symptoms of the condition (Long et al. 2016; Li et al. 2015).
How the reduction or absence of dystrophin ultimately leads to the clinical symptoms:
One of the key functions of dystrophin is to provide strength and support to the
muscle fibers by allowing it to attach the cytoskeleton of the fiber cells to its extracellular
matrix by forming protein complexes called the Dystrophin Associated Protein Complex
(DAPC). Reduction in this protein inside the muscle fiber cells causes the reduction of the
stiffness of the cell, increases the deformability of the sarcolemma (the tubular sheath that
covers the muscle fibers) as well as reduces the mechanical stability of the structural
component of the muscle called the costameres and its connections to the myofibrils nearby.
This can lead to the weakening of the muscles, reduction in the muscular mass and muscular
atrophy. The DAPC also helps to scaffold different signaling and channel proteins and has
functions in the process of regulating cell signals. Reduction in dystrophin thus affects the
process of cell signaling which further increases the risks of muscular atrophy and weakness
(Dial et al. 2018; Constantin 2014).

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Due to a lack of the expression of dystrophin in the muscle cells, a progressive change
to functionality of the proteins takes place. One of such change is the weakness of the
muscles. The weakness in the muscle is caused when the release of Calcium ions by the
sarcoplasmic reticulum decreases as well as due to change in the sensitivity of the calcium
ions as described by the Calcium Hypothesis (Constantin 2014). These in turn changes the
regulation of blood flow, lateral force transmission and can cause muscular damage (Yiu and
Kornberg 2015). Lateral force transmission also changes due to changes in the membrane
property and a an imbalance in the distribution of cytoskeleton protein and dystrophin.
Increased permeability of the membrane causes an increase in the levels of Creatinine Kinase
(CK) in the cells causing an influx of calcium ions which in turn impacts the membrane
permeability pathways thereby impacting the function of the muscle cells (Nigro and Piluso
2015). According to the mechanical hypothesis, a loss of dystrophin associated glycoprotein
complex (DGC) can cause contraction induced rupture of the muscle cell membrane that can
cause accumulation of serum proteins in the cytoplasm of muscle fibers (Yiu and Kornberg
2015)
In a healthy cell, dystrophin makes up 0.002% of the total protein content of the
muscle and its absence can lead to aberrant pathways of intracellular signaling which can
cause necrosis of the myofiber which then leads to increase in fatigue and weakness (Nigro
and Piluso 2015). The DAPC protein complex which helps to stabilize and strengthen the
muscle fiber, gets destabilized when there is an absence of dystrophin that causes damage to
the muscle fibers and membrane leakage. This shows that the absence dystrophin which plays
a key role in the maintenance of stability and strength of the muscle fibers leads to a
weakness of the muscle and its subsequent loss of mass as well as structure and stability
which ultimately cause the onset of the symptoms associated with DMD (Li et al. 2015; Yiu
and Kornberg 2015).

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References:
Aartsma-Rus, A., Ginjaar, I.B. and Bushby, K., 2016. The importance of genetic diagnosis
for Duchenne muscular dystrophy. Journal of medical genetics, 53(3), pp.145-151.
Angelini, C., 2018. Duchenne muscular dystrophy. In Genetic Neuromuscular Disorders (pp.
3-7). Springer, Cham.
Annexstad, E.J., Lund-Petersen, I. and Rasmussen, M., 2014. Duchenne muscular dystrophy.
Tidsskrift for den Norske laegeforening: tidsskrift for praktisk medicin, ny raekke, 134(14),
pp.1361-1364.
Constantin, B., 2014. Dystrophin complex functions as a scaffold for signalling proteins.
Biochimica et Biophysica Acta (BBA)-Biomembranes, 1838(2), pp.635-642.
Dial, A.G., Rooprai, P., Lally, J.S., Bujak, A.L., Steinberg, G.R. and Ljubicic, V., 2018. The
role of AMP-activated protein kinase in the expression of the dystrophin-associated protein
complex in skeletal muscle. The FASEB Journal, 32(6), pp.2950-2965.
Emery, A.E., Muntoni, F. and Quinlivan, R.C., 2015. Duchenne muscular dystrophy. OUP
Oxford.
Li, H.L., Fujimoto, N., Sasakawa, N., Shirai, S., Ohkame, T., Sakuma, T., Tanaka, M.,
Amano, N., Watanabe, A., Sakurai, H. and Yamamoto, T., 2015. Precise correction of the
dystrophin gene in duchenne muscular dystrophy patient induced pluripotent stem cells by
TALEN and CRISPR-Cas9. Stem cell reports, 4(1), pp.143-154.
Long, C., Amoasii, L., Mireault, A.A., McAnally, J.R., Li, H., Sanchez-Ortiz, E.,
Bhattacharyya, S., Shelton, J.M., Bassel-Duby, R. and Olson, E.N., 2016. Postnatal genome

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editing partially restores dystrophin expression in a mouse model of muscular dystrophy.
Science, 351(6271), pp.400-403.
Nigro, V. and Piluso, G., 2015. Spectrum of muscular dystrophies associated with
sarcolemmal-protein genetic defects. Biochimica et Biophysica Acta (BBA)-Molecular Basis
of Disease, 1852(4), pp.585-593.
Ousterout, D.G., Kabadi, A.M., Thakore, P.I., Majoros, W.H., Reddy, T.E. and Gersbach,
C.A., 2015. Multiplex CRISPR/Cas9-based genome editing for correction of dystrophin
mutations that cause Duchenne muscular dystrophy. Nature communications, 6, p.6244.
Yiu, E.M. and Kornberg, A.J., 2015. Duchenne muscular dystrophy. Journal of paediatrics
and child health, 51(8), pp.759-764.