Muscle Anatomy and Genetics
This section contains information about different muscle types, with emphasis on skeletal muscle. We will also go over the structure and function of muscle tissue. Finally, as muscle composition is determined by our genes, a brief introduction to certain genetics concepts will be presented.
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Muscle tissue is specialized for contraction and movement and it is found in two main forms: smooth and striated. Smooth muscle is present in those body systems that are under involuntary control. The digestive tract and the respiratory passages, among others, are made primarily of smooth muscle. Striated muscle is present in the heart and in the muscles that control our movements and breathing. Striated muscle owes its name to the interesting array of bands that becomes visible at the microscopic level. The origin and importance of these bands will be discussed further into this section. Striated muscle can be divided into two sub-types: cardiac muscle and skeletal muscle. Cardiac muscle, as the word implies, makes up the walls of the heart. Skeletal muscle is connected with the nerves, and because movement of these muscles can be consciously controlled, it is known as voluntary muscle. Most skeletal muscle is attached to our skeleton (hence its name) by a special form of tissue called tendons. In the Beggs Lab, we focus on the study of conditions that are caused by primary defects of skeletal muscle structure and function. These disorders are also known as myopathies. For a schematic representation of the different types of muscle tissue, see Figure 1 below.
Like any type of muscle, skeletal muscle is made of specialized cells called myofibers. Myofibers contain bundles of even smaller, thread-like structures called myofibrils. The myofibrils make up the machinery that allows movement and the use of force in daily activities. They contain many different specialized proteins that assemble together in a highly organized manner to form "thick filaments" and "thin filaments". The interaction between the proteins that form the thick and the thin filaments is what generates muscle contraction.
In summary, skeletal muscle is made of fibers, fibers are made of myofibrils, and myofibrils are made of proteins, which in turn form the thick filaments and the thin filaments. Figure 2 summarizes the elaborate composition of muscle tissue.
As stated at the beginning, when striated muscle is examined under a microscope, a distinct repeating pattern of bands can be observed. Each repeating unit (also known as the sarcomere), formed by the Z, I, A, H, and the M bands, is the product of the interaction between the proteins that form the thick filaments and the thin filaments. One of the goals of our lab is to characterize the proteins that form the sarcomere (sarcomeric proteins), hoping to identify new genes that are associated with disorders of muscle contraction.
Research has already unraveled many of the sarcomeric proteins that are responsible for skeletal muscle contraction. The names of some of these proteins are actin, myosin, troponin, tropomyosin, and nebulin. When skeletal muscle fibers receive a nerve impulse, these proteins (and others yet to be identified) are believed to change their shape and position. The thick filaments pull on and slide along the thin filaments, causing the sarcomere to shorten and the muscle to contract.
Just like the rest of the proteins in the body, instructions to make the sarcomeric proteins are encoded by different genes in the DNA. The DNA is actually a long string formed by four chemicals, namely, Adenine, Guanine, Cytosine, and Thymine (A, G, C, and T). The order in which these chemicals are found is what determines the genetic code, or sequence. A change in this order (i.e. mutation) results in a change of the encoded protein.
Proteins play many roles in the body. For example, they give the cues for development, determine eye color, and help in food digestion, among others. Proteins are essential for body function and therefore, certain protein alterations can cause disease. In particular, alterations in any of the sarcomeric muscle proteins can potentially cause muscle disease. For example, alterations in actin are known to cause nemaline myopathy, a disease of skeletal muscle that causes low muscle tone, muscle weakness and respiratory difficulties, among others. Protein alterations are caused by gene changes (mutations).
At this point, it is worth mentioning that not all genetic changes have an impact on our health. Although the vast majority of the DNA is very similar among different people, some parts of the DNA may vary. All human beings are different. People have different skin color, hair, and eye color. The reason for these differences is that everybody's DNA is different. Most of the time, the DNA changes that produce different skin or eye colors do not have an impact on our health. In addition, many DNA changes are "silent", having no known effects on our development.
"Silent" DNA changes do not cause disease or differences between individuals. When a new mutation is found in an individual, it is important to confirm whether the DNA change is disease causing or not. In the Beggs lab, we do that by comparing samples from affected to non-affected family members, as well as to samples from members of the general population. If a mutation is present in both affected and non-affected family members, then we are likely to conclude that this mutation does not cause disease.
A genetic change that interferes with somebody's health must be significant enough so that the function of the protein encoded by the gene becomes altered. The outcome of a particular gene alteration is also dependent on how essential to the body is the protein made by that gene. Certain mutations in the genes encoding actin, nebulin, troponin, and tropomyosin cause nemaline myopathy, a disease associated with muscle weakness and respiratory problems. Similarly, mutations in the gene for myotubularin 1 cause X-linked myotubular myopathy, a severe condition associated with muscle weakness, skeletal problems, and fatigability. Specific genetic cause(s) for multiminicore disease, congenital fiber-type disproportion (CFTD), as well as certain non-specific myopathies are the subject of current research.
Identification of mutations may lead to better understanding of basic muscle biology, will allow for the development of improved diagnostic tests, and will hopefully lead to insights into therapies. This is why the Beggs lab is actively looking for congenital myopathy-causing genetic changes.
Patients with nemaline myopathy develop rods (dark structures) that disrupt the sarcomeres.