Desmin: Its Role in Desminopathy
Introduction
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
Hypertrophic cardiomyopathy is an inherited autosomal-dominant pattern affecting nearly 1 in 500 people, affecting both men and women equally. Which makes it the most “common genetic heart disease in the United States” [5] Many studies have been done on the causes of this disease. Research has shown the mutations of between 10 to 13 sarcomeric proteins are associated with HCM. Each mutated gene has a different pathological characteristic.
Muscle fibres, as shown in Diagram 1, consist of myofibrils, which contain the proteins, actin and myosin, in specific arrangements . The diagram illustrates how a muscle is made up of many fascicles, which in turn are made up of many endomysiums, and within them, many muscle fibres. Each muscle fibre is made up of many myofibrils that consist of sarcomeres bound end on end . Actin is a thin filament, about 7nm in diameter, and myosin is a thick filament, about 15nm in diameter , both of which reside in the sarcomere. They are held together by transverse bands known as Z lines . Diagram 2 shows actin and myosin filaments within a sarcomere, and the Z lines that connect them.
Rationale, Significance and Hypothesis. An extrinsic factor, which exerts a dominant influence on skeletal muscle fiber phenotype, is the nervous system. Buller et al. (1960) elegantly demonstrated the plastic nature of skeletal muscle fibers in response to changes in innervation type. Later, Lφmo and Westgaard (Lφmo and Westgaard, 1974; Westgaard and Lφmo, 1988) demonstrated that depolarization of muscle with specific patterns and frequencies of electrical activity are sufficient to cause changes in mature muscle fiber phenotypes. However, how myofibrillar gene expression and structural organization is affected by the frequency of impulses during activity, the amount of activity over time, or other characteristics of patterned activity is essentially unknown. To answer these questions will require the isolation and study of subsets of muscle-specific proteins in relation to different electrical activation patterns in vivo, an issue that cannot be easily addressed in preparations currently used in the study of muscle development and maintenance. However, using novel in vivo approaches can, in part, circumvent this difficulty.
Occurrence of muscle dystrophy is estimated to be one in 3-4,000 male births. There are also about 15,000 muscular dystrophy patients in the United States today with this disease. Those who have muscular dystrophy are missing the protein called dystrophin. Before scientists ever discovered the missing protein, the tested carriers for the disease had a high presence of elevated serum levels of creatine and phosphokinase. The disease can now be found for a prenatal diagnosis.
Each form has other subtypes, one subtype of LGMD 2 is known as LGMD 2B (dysferlinopathy). In metabolism this disorder is caused by a mutation in the dysferlin Gene (DYSF). According to Keller Metabolism and Proteomic of Limb Girdle Muscular Dystrophy Type 2B (Dysferlinopathy) dysferlin gene is on chromosome 2p13 encoding the 230 kDa protein dysferlin (Keller, 2016). As stated earlier, patients with LGMD show signs of weakness in the muscle more proximal to the body. Affected hip, shoulder and back muscles are physical signs of LGMD that can be seen by Doctors. Dysferlin, which is also known as dystrophy-associated fer-1-like protein; a protein that in humans is encoded by the DYSF gene (Keller, 2016). Dysferlin is correlated with skeletal muscle repair and plays a critical role in the cell repair processes in
Myofibrils are made up of long proteins that include myosin, titin, and actin while other proteins bind them together. These proteins are arranged into thin and thick filaments that are repetitive along the myofibril in sectors known as sarcomeres. The sliding of actin and myosin filaments along each other is when the muscle is contracting. Dark A-bands and light I-bands reappear along myofibrils. The alignment of myofibrils causes an appearance of the cell to look banded or striated. A myofibril is made up of lots of sarcomeres. As the sarcomeres contract individually the muscle cells and myofibrils shorten in length. The longitudinal section of skeletal muscle exhibits a unique pattern of alternating light and dark bands. The dark staining, A-bands possess a pale region in the middle called the H-zone. In the middle of the H-zone the M-line is found, that displays filamentous structures that can join the thick filaments. The light-staining bands also known as I-bands are divided by thin Z-line. These striated patterns appear because of the presence of myofibrils in the sarcoplasm (IUPUI, 2016).
(Giarelli, Bernhardt, & Pyeritz, 2010, Lashley, 2007 ,Canadas et al., 2010). The mutant gene is found on an autosome consequently, the syndrome can affect males and females equally. While, only one copy of the mutant gene is necessary for the disorder to be present (Lashley, 2007). Fibrillin-1 is a large gene, made of complex glycoproteins that are responsible for the flexibility and strength of connective tissue (Giarelli, Bernhardt, & Pyeritz, 2010 & Gonzales, 2009). Fibrillin-1(FBN1) is most abundant in the cardiac, ocular and, skeletal system throughout the body. This glycoprotein can also be found in elastic and non- elastic tissues and is a chief component of microfibrils. Microfibrils maintain cellular bonds in the extracellular matrix and form the framework of elastic fibers in the aorta and ligaments of the musculoskeletal system and multiple organ systems (Keane & Pyeritz, 2008). These microfibrils consist of the structural parts that support the ligaments in the ocular lens and have a load-bearing role in elastic arteries (Chen & Buehler, 2010). As a result of the mutation in the FBN1 gene abnormalities occur in the microfibrils and can cause faulty connective tissue. The mutations were thought to create weakness of the aortic wall, lens dislocation, joint hyperlaxity and, widening
Currently, there are 9 major forms of muscular dystrophy which include: Myotonic, Becker, Limb-girdle, Facioscapulohumeral, Congenital, Oculopharyngeal, Distal, Emery-Dreifuss, and Duchenne muscular dystrophy (Mayo Clinic, 2014). For the purpose of this paper, the cause, as well as the impact of Duchenne muscular dystrophy on development, will be discussed.
The malfunction of the protein dystrophin is responsible for the symptoms of DMD. If the dystrophin gene functions correctly, the normal allele codes for the production of the protein dystrophin (“NCBI”). This is a high molecular weight protein, and it is in .002% of the total proteins. Normally, the dystrophin protein functions inside muscle cells, providing structural support. It anchors parts of the internal
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 caused by a mutated gene in the X chromosome. This flawed genes is passed on by the mother. However, most carrier of the gene do not show signs or symptoms of the disease. The The flawed gene causes the improper production of the protein dystrophin which is accompanied by “defective dystrophin-glycoprotein complex (DGC) in the sarcolemma and leads to progressive muscle degeneration” (Nakamura & Takeda, 2011). The Dystrophin protein is vital in providing a muscle integrity. Therefore, the absence of dystrophin production can lead to muscled atrophy.
This protein may play a role in the communication within cells, especially those of the heart, brain and skeletal muscles. It is believed that the protein is involved in the communication between cells and regulates the production and function of important structures inside muscles cells by interacting with other proteins. The DMPK gene is located on the long arm of chromosome 19 at position 13.3. It is between base pairs 45,769,708 and 45,782,556 making it 12848 base pairs long. It consists of a trinucleotide repeat of the nucleotide sequence CTG. Meaning that the nucleotides CTG are repeated multiple times. In a normal DMPK protein the number of CTG repeats ranges from 5-34. The mutation that causes myotonic dystrophy is known as trinucleotide repeat expansion, meaning it increases the number of times CTG is repeated in the gene. People with myotonic dystrophy can have 50 to 50,000 repeats, the more repeats an individual has the worse their symptoms are. The increased number of repeats produces an expanded version of mRNA, which then forms clumps inside the cell that interfere with the production of many other proteins. These clumps prevent muscle cells and cells in other tissues from functioning
Muscle myopathy is a disease in which the skeletal muscle in human body weakens and difficult to move (Carnell et al., 2012). This disease can also affect the smooth muscle in respiratory tract that leads to shortage in oxygen and carbon dioxide accumulation in blood. This disease is caused by the mutation of ATP-binding activity of actin filaments. Therefore, muscle contraction cannot occur, being that ATP is essential for the muscle to contract. There is no effective cure for this disease (NINDS, 2015). However, some treatments can be done to overcome the weakness of the muscle. Treatment for this disease is based on the muscle condition of the patient. Some physical therapy and using brace as a support of the muscle can help the patient who
The morphology and functions of specialized cells within tissues such as muscle requires the unique organization of the actin cytoskeleton this actin cytoskeleton rely on actin network, vinculin, to locked the filamentous actin (F-actin) to the membrane.1 Vinculin is a structural protein that plays an important role in multiple protein assemblies linking the extracellular matrix to actin cytoskeleton.2 Vinculin is an 116 kDa cytoskeletal protein linked to cell-matrix and cell-cell junctions. It is said to work as one of a few interconnecting proteins required to secure the F-actin to the membrane. Vinculin has a helical head and tail domains attached by a flexible proline-rich linker.3 The head and tail domain mingle in an autoinhibitory manner, blocking binding to a significant number of prospective ligands.4 In addition to vinculin, there is metavinculin (MV), which is a splice variant of vinculin. MV is a muscle-specific splice of vinculin and is expressed in smooth and cardiac muscle tissue. MV is linked to dilated cardiomyopathy (DCM) deficiency which is a form of heart disease.
The malfunctioning organelle is the microfilaments. First of all, the microfilaments are known for maintaining the shape of the cell and allowing organelles to move within the cell (Mader, 60). One can start by saying that when there is any failure in the microfilaments then the organelles of the cell will not properly move, shown in the “impaired intracellular movement of materials”, as stated in the laboratory results. Moreover, microfilaments are compared to the bones and muscles of the cell. Focusing on muscles, actin filaments’ role in the muscle cell is to strengthen it; therefore, any malfunction will lead to a weaker muscle, seeing the issue of “muscle weakness” in the patient’s history and even “muscle loss and deformity” in the physical