Coupling muscle activation

McCampbell A, Taye AA, Whitty L, Penney E, Steffan JS, Fischbeck KH (2001) Histone deacetylase inhibitors reduce polyglutamine toxicity. Proc Natl Acad Sci U S A 98(26) 15179-15184 Mejat A, Ramond F, Bassel-Duby R, Khochbin S, Olson EN, Schaeffer L (2005) Histone deacetylase 9 couples neuronal activity to muscle chromatin acetylation and gene expression. Nat Neurosci 8(3) 313-321... 

Dantrolene is a hydantoin class of anticonvulsant that acts outside the central nervous system to produce skeletal muscle relaxation by interfering with excitation contraction coupling. In normally contracting muscle, activation of the ryanodine receptor within the muscle fiber results in calcium release from the sarcoplasmic reticulum and subsequent muscle contraction. Dantrolene interferes with the release of calcium from the sarcoplasmic reticulum by interfering with the ryanodine receptor. The release of calcium in smooth and cardiac muscle is under different control consequently, dantrolene primarily affects skeletal muscle. 

Chemistry, mechanism, and effects Glucagon is the product of the A cells of the endocrine pancreas. Like insulin, glucagon is a peptide but unlike insulin, glucagon acts on G protein-coupled receptors. Activation of glucagon receptors, which are located in heart, smooth muscle, and liver, stimulates adenylyl cyclase and increases intracellular cAMP. This results in increases in the heart rate and the force of contraction, increased hepatic glycogenolysis and gluconeogenesis and relaxation of smooth muscle. The smooth muscle effect is particularly marked in the gut. 

Forces play an integral role in the dynamic behavior of all human mechanics. In terms of human movement, forces can be defined as intrinsic or extrinsic. For example, a couple about a particular joint will involve the intrinsic muscle and frictional forces as well as any extrinsic loads sustained by the system. If the influence of intrinsic muscle activity within the system is to be considered, the location of the insertion points for each muscle must be determined to properly solve the equations of motion. 

Excitation of smooth muscle via alpha-1 receptors (eg, in the utems, vascular smooth muscle) is accompanied by an increase in intraceUular-free calcium, possibly by stimulation of phosphoUpase C which accelerates the breakdown of polyphosphoinositides to form the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 releases intracellular calcium, and DAG, by activation of protein kinase C, may also contribute to signal transduction. In addition, it is also thought that alpha-1 adrenergic receptors may be coupled to another second messenger, a pertussis toxin-sensitive G-protein that mediates the translocation of extracellular calcium. 

However, release of ADP and P from myosin is much slower. Actin activates myosin ATPase activity by stimulating the release of P and then ADP. Product release is followed by the binding of a new ATP to the actomyosin complex, which causes actomyosin to dissociate into free actin and myosin. The cycle of ATP hydrolysis then repeats, as shown in Figure 17.23a. The crucial point of this model is that ATP hydrolysis and the association and dissociation of actin and myosin are coupled. It is this coupling that enables ATP hydrolysis to power muscle contraction. 

Jervis used porous silica coated with chemisorbed polyacrylhydrazide for immobilization of adenosine monophosphate (AMP) [117]. After periodate oxidation of its ribose residue the ligand was coupled to the carrier and used for isolation of lactate dehydrogenase from rabbit muscle. The specific capacity was 2 mg of protein/g adsorbent with a ligand content of 10 pmol/g, whereas recovery of enzymatic activity after elution was 85%. Hipwell et al. [118] found that for effective binding of lactate dehydrogenases on AMP-o-aminoalkyl-Sepharose the spacer arm length required at least 4 methylene links. Apparently, a macromolecule of polyacrylhydrazide acts itself like an extended spacer arm and thus allow AMP to bind the enzyme. 

Excitation-contraction coupling (EC coupling) is the mechanism underlying transformation of the electrical event (action potential) in the sarcolemma into the mechanical event (muscle contraction) which happens all over the muscle. In other words, it is the mechanism governing the way in which the action potential induces the increase in the cytoplasmic Ca2+ which enables the activation of myofibrils. 

Neuromedin U is a neuropeptide which is widely distributed in the gut and central nervous system. Peripheral activities of neuromedin U include stimulation of smooth muscle, increase in blood pressure, alteration of ion transport in the gut, control of local blood flow and regulation of adrenocortical function. The actions of neuromedin U are mediated by G-protein coupled receptors (NMU1, NMU2) which are coupled tO Gq/11. 

Four different localizations of fatigue can be identified (a) decreased central command (b) decreased activation of the muscle membrane and the T-tubular system (c) decreased Ca release from the SR and (d) decreased response to the Ca release by the contractile proteins. The first two are partly extra-muscular while c and d are intramuscular responses to the excitation of the muscle membrane and often defined as excitation-contraction coupling. 

From this brief summary of excitation-contraction coupling it is obvious that Ca is an important link between the activated membrane and the contractile proteins, and thus a regulator of tension development. Westerblad et al. (1991) defined three factors which explain the force decrease in fatigued muscle reduced Ca " release from the SR, reduced Ca sensitivity of the myofilaments, and reduced maximum Ca -activated tension. 

---