Skeletal Muscle Contraction - Essay Example

? SKELETAL MUSCLE CONTRACTION Skeletal Muscle Contraction Skeletal Muscle constitutes 40% of themuscles in the human body while the smooth muscle and the cardiac muscle form 10% of the entire muscle content. Skeletal muscle fibres are the voluntary group of muscles that are range from the small muscles in the eyes to the large and powerful muscles in the calf that cause leg movements. Anatomically skeletal muscles are composed of a number of fibres and each fibre is then further composed of smaller sub-units. These smaller fibres are called as myofibrils. The cell membrane of the muscle fibre is called as the sarcolemma which fuses at the end of each muscle fibre with the tendon and hence inserts the muscle into the bone (Guyton & Hall 2006; Sherwood 2007). The normal physiological mechanism of skeletal contraction brings about the voluntary movements of our body like eye movements, walking and sitting. Disruption of the skeletal muscle contraction caused by genetic abnormalities results in muscular weakness and wasting over a passage of time and this is termed as muscular dystrophy (Tiidus 2008). The mechanism of skeletal contraction is understood better at the molecular level and by the biochemical changes that occur with each contraction. Fig1: The anatomy of the muscle fibre shows myofibrils and the dark and light bands on electron microscopy (Chiras 2012). To understand the muscular contraction, it is important to first know about myosin and actin filaments. Each myofibril is composed of 1500 myosin and 3000 actin filaments. On electron microscopy, they are visible as alternate light and dark bands. The light bands are the actin filaments, known as I bands, and the dark ones are myosin filaments, termed as A bands. At the end, the actin filaments are attached to Z discs. The unit between two Z discs is termed as a “sarcomere”. The muscular contraction is initiated by a nerve impulse that reaches the muscle fibres through its motor nerve endings. The release of acetylcholine, a neurotransmitter, causes the start of the ion exchange through the “acetylcholine-gated channels” present at the muscle fibre membranes. Sodium ions diffuse into the interior of the muscle membrane causing the initiation of an action potential. The travelling of the action potential across the muscle fibre causes the release of the calcium ions from the sarcoplasmic reticulum, which is otherwise stored in the reticulum. The calcium ions are the triggering factors for the actin/ myosin filament contraction which is the basic contractile process taking place within the muscle fibre. Within a small fraction of a second, the calcium ions diffuse back into the reticulum and with the absence of calcium the contraction process also stops (Guyton & Hall 2006). Cross-bridges are the areas where the thick filaments as well as the thin filaments overlap each other. Thick filaments are the myosin filaments while actin, troponin and tropomyosin constitute the thin filaments. Actin filaments can bind to the myosin filaments only through special binding sites which can only lead to the contractile process. Tropomyosin is present on the actin filament in such a manner that they block the binding sites for contraction. Troponins are a protein complex which has three binding sites for the tropomyosin, calcium ions and the actin filament each. Troponin molecules in their calcium unbound condition lead to the position of tropomyosin in a manner that it blocks the actin binding sites for myosin filament. These two proteins that is troponin and tropomyosin are also referred to as regulatory proteins owing to their ability to control and regulate the process of the contraction of muscles (Sherwood 2007). Fig 2: A diagrammatic description of the actin filament and the troponin-tropomyosin complex (Macintosh et al 2006). The molecular mechanism of skeletal muscle contraction is explained by the sliding filament mechanism. During the relaxed state, the actin filaments do not overlap each other. Calcium ions are responsible for generating the force required for actin sliding movements and the energy is obtained by the breakdown of adenosine triphosphate (ATP) to adenosine diphosphate (ADP). The myosin filament head also acts as an ATPase enzyme causing the cleavage of ATP for energy production. When calcium ions are released the inhibitory action of the troponin-tropomyosin complex on the actin filament binding site is removed. This results because the binding of calcium to troponin binding site causes it to undergo a structural change causing the pulling of tropomyosin from the binding site and hence “uncovering” it. With the activation of actin filaments, the myosin and actin filament are attracted to each other (Guyton & Hall 2006). The contractile process that occurs by the attractive forces between actin and myosin is explained by the ratchet theory or “walk-along theory”. The attachment of the head of the myosin to the actin filament leads to a structural change in the myosin head resulting in its tilting. The tilted head pushes the actin filament along with itself termed as the “power stroke”. With one power stroke, the head detaches from one active site and moves to the next active site; pushing it inwards and hence another power stroke is produced. This process keeps on happening causing repeated power strokes leading to the contractile process (Guyton & Hall 2006). ATP is crucial to bring about the cross-bridge overlapping between the thick filaments of actin and the thin filaments of myosin. Without ATP, this overlapping cannot take place. This is explained by “rigor mortis” or stiffness of death. The dead cells are unable to produce ATP in fresh amounts and the actin myosin filaments remain interlinked in the state of contraction causing stiffness and are resolved by the protein degradation taking place after many days or weeks (Sherwood 2012). The sarcomere contractility produces tension in the unit which is transmitted to the bone through the connective tissues or the tendons. The shortening and tightening of the muscle fibres causes the bone to move along with the muscle while lifting weights or moving. The ATP supplies for muscle contraction are present for direct use and the pathways that are supplying additional ATP for this purpose continuously are the desphosphorylation of creatine phosphate, glycolysis and oxidative phosphorylation (Sherwood 2012). Muscular dystrophy is an inherited group of diseases that is basically caused by gene defects which are responsible normally for the skeletal muscle activity. These disorders present in the early years of life i.e. in childhood and are progressively degenerative disorders of muscle fibres. The word dystrophy literally means abnormal nutrition and hence the word muscular dystrophy points out towards the deficient nutrition of the muscle fibres leading to weakness. The types of muscle and the site of muscle affected depend on the different types of muscular dystrophies. Skeletal muscles are mostly affected in the muscle dystrophies and the heart and the gut muscles are spared. Proteins are present in normal amounts in the muscle fibres. These include dystophin, caveolin, sarcoglycans and merosins. If due to any genetic defect these proteins are disrupted or absent they can result in the breakdown of the membrane of the muscle fibres. If the muscle membrane is disrupted it results in either leakage of ions or other extracellular materials into the muscle fibres or lack of muscle fibre bulk and power for the contractile process. Due to excessive leakage, calcium ions can also enter in increased amounts causing muscle cell damage. Histological changes show variations in muscle fibre sizes, degenerative changes and the muscle is progressively filled with fibro-fatty tissue (Emery 2008; Kumar et al 2007). Fig 3: A diagram illustrating the various proteins interlinked with the sarcolemma and the extracellular matrix (Emery 2008). The classification of muscle dystrophies is made on the basis of gene location and the protein defect that it causes. The Duchenne muscle dystrophy and the Becker muscular dystrophy have an X-linked pattern of inheritance and the dystrophin protein is affected. Limb Girdle muscular dystrophies are a heterogeneous group of autosomal inherited muscular dystrophies that majorly affect the muscles of the pelvic girdle and the shoulder. It is further classified into autosomal dominant and recessive subtypes called as LGMD1 and LGMD2. The proteins affected in this type of muscular dystrophy include the myotilin, lamin, caveolin-3, numerous types of sarcoglycans and telethonins. Congenital muscular dystrophies present within the first few months of life or even at birth. The babies are commonly referred as “floppy babies” and mental retardation and brain abnormalities are common in this type. Myotonoic dystrophies are characterized by a persistent or sustained muscular contraction which is involuntary and causes stiffness of muscles. This starts in the second to fifth decade of life and affects even the heart, lens, testes and other organs of the body (Gilman 2007; Kumar et al 2007). Duchenne muscular dystrophy (DMD) first described by Edward Meryon in 1852 is a critical muscle wasting disorder that has a higher predisposition towards males. It is characterized by progressive deterioration of the contractility of the muscles because of the genetic defect causing absence of dystrophin protein. The Duchenne Muscular dystrophy (DMD) affects approximately one out of every 3500 males who are born alive. Females with signs and symptoms as severe as males are very uncommon and around 10% of the females manifest as carriers with very minor muscle weakness symptoms (Tiidus 2008; Bushby et al 2005). DMD manifests itself in the early years of life and the symptoms become evident at the age of five and progressive muscle weakness and wasting up reaches its maximum by 10-12 years. The weakness becomes so severe at this age that the child is restricted to a wheelchair. Most of the cases have poor prognosis and the death occurs till the early 20s (Kumar et al 2007). The genetic pathogenesis of the disease is initiated by the abnormalities in the gene located on the short arm of the X chromosome (Xp21). Dystrophin protein is expressed by this gene and is located in all the muscles types of the body. This protein is very important as it is even present in the brain and the nerves of the human body. Dystrophin is present in the inner layer of the skeletal muscle membrane that is the sarcolemma. Dystrophin plays the important role of transferring the force of contraction from the muscle to the connective tissue and helps in maintaining the structure and function of the skeletal muscle fibre. In the case of DMD, the dystrophin gene is absent rendering the muscle increasingly permeable to molecules and hence there is a constant movement of molecules into and outside the myocyte. Markers like increased creatine kinase in the serum and presence of serum albumin and immunoglobulin in the myocyte highlight the increased fragility and leakiness of the muscle fibres. The histology of the muscle fibre gives evidence of muscle hypertrophy and atrophy causing variations in muscle lengths and replacement of the muscle fibre progressively with non-contractile fat (Tiidus 2008; Kumar et al 2007). Clinical assessment is very important for the diagnosis of DMD. The clinical signs start appearing during the third or fourth decade of life. It starts as proximal muscle weakness which primarily affects the pelvic and shoulder girdle muscles. Pseudo-hypertrophy is a prominent feature which occurs in the calf muscles when the muscle fibre is replaced by fibro-fatty tissue as an outcome of muscle wasting. Mental retardation might be present due to lack of dystrophin in the brain. Respiratory complications are also seen along with cardiac arrhythmias and gut complications. Death is caused mainly by the respiratory complications (Rubin & Strayer 2007). Diagnosis of the DMD is made by serum creatine kinase levels which are elevated mostly 10-20 times above the normal limit. This is the first laboratory sign that a doctor should observe and this should be followed by further investigations to reach to a definitive conclusion with regard to the diagnosis. Genetic testing should be done to check for the deletion of the dystrophin gene and 70% of the patients give positive results. Muscle biopsy is the next step in the laboratory diagnosis and a dystrophin analysis of the muscles should be done. During the diagnostic procedures it is important to also test the mother to check if she is a carrier of the disease. Parents should be supported and kept aware of the condition throughout the diagnostic process as this is a critical time for them (Bushby et al 2005). Fig 5: Children with DMD have hypertrophied calf muscles and have difficulty in rising up due to proximal muscle weakness known as Gower’s sign (Passarge 2001). The management of the DMD focuses on the muscle wasting and weakness affecting various sites and to prevent any complications. Glucocorticosteroids are the highly recommended treatment choice for muscle weakness and wasting. Prednisolone daily dosage of 0.75 mg/kg/day is the recommended dosage regimen. Physiotherapy is also helpful. 90% of the patients suffering from DMD develop scoliosis and scoliosis surgery is helpful in managing this complication. Respiratory management includes regular surveillance, chest infection control and controlling hypoventilation at night. In cases of cardiomyopathies in DMD patients ECG and echocardiograms should be regularly performed and in case of any detection of symptoms, beta blockers, diuretics and ACE-inhibitors should be started to prevent heart failure (Bushby et al 2005). As stated by a DMD patient, muscular dystrophy exposes the male children not only to medical complications but also to social and environmental hindrances. They feel alone and isolated from their family and friends. They have difficulties in establishing sexual relationships, have the fear of death and are mostly dependant on others. They are mostly bed-ridden or on wheel-chairs making them unable to mingle with others and decreasing their comfort level with others. Health professionals should not only deal with the medical illness but also with the emotional dilemmas and anxiety these children face (Spies et al 2010). Muscle dystrophy includes a vast group of disorders caused by abnormalities in normal muscle contraction and functioning. Out of the many types, Duchenne Muscular dystrophy is one of the most common ones and requires rehabilitation and supportive management throughout the life span of the patient. Bibliography BUSHBY, K., BOURKE, J., BULLOCK, R., EAGLE, M., GIBSON, M., & QUINBY, J. (2005). The multidisciplinary management of Duchenne muscular dystrophy.CURRENT PAEDIATRICS. 15, 292-300. CHIRAS, D. D. (2012). Human biology. Sudbury, MA, Jones & Bartlett Learning. EMERY, A. E. H. (2008). Muscular dystrophy. Oxford, Oxford University Press. GUYTON, A. C., & HALL, J. E. (2006). Textbook of medical physiology. Philadelphia, Penns, Elsevier Saunders. GILMAN, S. (2007). Neurobiology of disease. 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