Skeletal muscle specificity

FIGURE 11-7 Gene structure of AChE. Alternative cap sites in the 5 end of the gene allow for alternative promoter usage in different tissues. Skeletal-muscle-specific regulation is controlled by the intron region between Exons 1 and 2. Exons 2, 3 and 4 encode an invariant core of the molecule that contains the essential catalytic residues. Just prior to the stop codon, three splicing alternatives are evident 1, a continuation of exon 4 2, the 4-5 splice and 3, the 4-6 splice. The catalytic subunits produced differ only in their carboxy-termini and are shown in the lower panel. (Modified with permission from reference [24].)... 

Garvey, S.M., Rajan, C., Lemer, A.P., Frankel, W.N. and Cox, G.A., 2002, The muscular dystrophy with myositis (mdm) mouse mutation disrupts a skeletal muscle-specific domain of titin, Genomics, 79, 146-149... 

Sorimachi, H., Ono, Y., Suzuki, K., 2000, Skeletal muscle-specific calpain, p94, and connectin/titin their physiological junctions and relationship to limb-girdle muscular dystrophy type 2A, Adv. Exp. Med. Biol., 481, 383-95... 

Skeletal muscle relaxants are used to treat conditions associated with hyperexcitable skeletal muscle— specifically, spasticity and muscle spasms. Although these two terms are often used interchangeably, spasticity and muscle spasms represent two distinct abnormalities. The use of relaxant drugs, however, is similar in each condition because the ultimate goal is to normalize muscle excitability without a profound decrease in muscle function. Considering the number of rehabilitation patients with muscle hyperexcitability that is associated with either spasm or spasticity, skeletal muscle relaxants represent an important class of drugs to the rehabilitation specialist. 

Fig. 2. (A) Analysis of human adult skeletal (HAS) and cardiac muscle (HAC) transcripts by an oligonucleotide array representing all 363 exons of the human titin gene. Left Comparison of results obtained with HAS (top) and HAC (bottom) transcripts reveals large blocks of exons that are only positive in skeletal muscle. Right Examples of constitutively expressed exons (exon 5 and 7), cardiac specific exons (11 and 49), and skeletal muscle specific exons (156 and 210). 5MM a 50mer from exon 5 including five base-pair mismatches as a control for hybridization...

Tjfam-deficient mice (Heart and skeletal muscle-specific Tfam knockout) MtDNA depletion, respiratory chain deficiency Dilated cardiomyopathy, atrioventricular heart conduction blocks W4... 

The voltage-gated CLC family in mammals contains at least nine different genes, encoding CLC-l-CLG-7, CLC-0, GLG-Ka (GLG-Kl), and CLC-Kb (CLC-K2). All voltage-gated CLCs have a common structure, with intracellular N- and G-termini and 10 to 12 TM domains. Mutations in the skeletal muscle-specific CLC-1 lead to increased excitability, suggesting that CLCs control the... 

Liao, W., Hong, S. H., Ghan, B. H., Rudolph, F. B., Clark, S. C., and Chan, L. (1999). APOBEC-2, a cardiac-and skeletal muscle-specific member of the cytidine deaminase supergene family. Biochem. Biophy.s. Res. Comm. 260, 398-404. 

The absorption of sulfonylureas from the upper gastrointestinal tract is faidy rapid and complete. The agents are transported in the blood as protein-bound complexes. As they are released from protein-binding sites, the free (unbound) form becomes available for diffusion into tissues and to sites of action. Specific receptors are present on pancreatic islet P-ceU surfaces which bind sulfonylureas with high affinity. Binding of sulfonylureas to these receptors appears to be coupled to an ATP-sensitive channel to stimulate insulin secretion. These agents may also potentiate insulin-stimulated glucose transport in adipose tissue and skeletal muscle. 

The trigger for all musele eontraetion is an increase in Ca eoneentration in the vicinity of the muscle fibers of skeletal muscle or the myocytes of cardiac and smooth muscle. In all these cases, this increase in Ca is due to the flow of Ca through calcium channels (Figure 17.24). A muscle contraction ends when the Ca concentration is reduced by specific calcium pumps (such as the SR Ca -ATPase, Chapter 10). The sarcoplasmic reticulum, t-tubule, and sarcolemmal membranes all contain Ca channels. As we shall see, the Ca channels of the SR function together with the t-tubules in a remarkable coupled process. 

Dihydropyridine receptor (DHPR) is a member of voltage-dqiendent Ca2+ channels (CaVi, L-type), which specifically binds to dihydropyridine derivatives, a group of the Ca2+ channel blockers. Cav 1.1 works as the voltage sensor for skeletal muscle contraction, and Cay 1.2, as Ca2+-influx channel for cardiac muscle contraction. 

Uptake of LCFAs across the lipid-bilayer of most mammalian cells occurs through both a passive diffusion of LCFAs and a protein-mediated LCFA uptake mechanism. At physiological LCFA concentrations (7.5 nM) the protein-mediated, saturable, substrate-specific, and hormonally regulated mechanism of fatty acids accounts for the majority (>90%) of fatty acid uptake by tissues with high LCFA metabolism and storage such as skeletal muscle, adipose tissue, liver,... 

Tissue-Specific Expression. In adult rodents, PPAR.a is expressed in liver, kidney, intestine, heart, skeletal muscle, retina, adrenal gland, and pancreas. In adult human, PPARa is expressed in the liver, heart, kidney, large intestine, skeletal muscle (mostly slow-twitch oxidative type I fibers), and in cells of atherosclerotic lesions (endothelial cells, smooth muscle cells, and monocytes/macrophages). Therefore, regardless of... 

Tissue-Specific Expression. In the adult rodent, PPARy is expressed in brown and white adipose tissue, and at lower levels in intestine, retina, skeletal muscle, and lymphoid organs. In human, PPARy is most abundantly expressed in white adipose tissue and at lower levels in skeletal muscle, the heart, and liver, but not in lymphoid tissues, although PPARy has been identified in macrophages in human atheromas. 

Ryanodine is a neutral plant alkaloid from Ryania speciosa and was used as an insecticide. It also has been well known by the characteristic action on mammalian skeletal muscle of slowly developing, and intensive and irreversible contracture. Ryanodine binds specifically to the open RyR channel at the stoichiometry of 1 mol/mol homotetramer with a high affinity (ATD nM) and leads the channel to ryanodine modified state characteristic of long-lasting subconductance ( 50% of normal) opening. At higher concentration, it blocks the channel. 

The smooth muscle cell does not respond in an all-or-none manner, but instead its contractile state is a variable compromise between diverse regulatory influences. While a vertebrate skeletal muscle fiber is at complete rest unless activated by a motor nerve, regulation of the contractile activity of a smooth muscle cell is more complex. First, the smooth muscle cell typically receives input from many different kinds of nerve fibers. The various cell membrane receptors in turn activate different intracellular signal-transduction pathways which may affect (a) membrane channels, and hence, electrical activity (b) calcium storage or release or (c) the proteins of the contractile machinery. While each have their own biochemically specific ways, the actual mechanisms are for the most part known only in outline. 

Proteins play an important role in movement at both the organ (eg, skeletal muscle, heart, and gut) and cellular levels. In this chapter, the roles of specific proteins and certain other key molecules (eg, Ca ) in muscular contraction are described. A brief coverage of cyto-skeletal proteins is also presented. 

The entry rate of glucose into red blood cells is far greater than would be calculated for simple diffusion. Rather, it is an example of facilitated diffiision (Chapter 41). The specific protein involved in this process is called the glucose transporter or glucose permease. Some of its properties are summarized in Table 52-3-The process of entry of glucose into red blood cells is of major importance because it is the major fuel supply for these cells. About seven different but related glucose transporters have been isolated from various tissues unlike the red cell transporter, some of these are insidin-dependent (eg, in muscle and adipose tissue). There is considerable interest in the latter types of transporter because defects in their recruitment from intracellular sites to the surface of skeletal muscle cells may help explain the insulin resistance displayed by patients with type 2 diabetes mellitus. 

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