desmosterol and Myotonia

Topics: Animals; Azacosterol; Carboxylic Acids; Chlorides; Clofibrate; Desmosterol; Humans; Iodides; Membrane Potentials; Muscles; Myotonia; Rats

Previous spin-label and electromyographic experiments with rats fed 20,25-diazacholesterol, an inhibitor of the biosynthetic conversion of desmosterol to cholesterol, demonstrated an increased erythrocyte membrane fluidity and myotonia, a prolonged muscle contraction upon stimulation. The current studies with rats showed normal erythrocyte fluidity in animals fed 20,25-diazacholesterol but maintained on a high-cholesterol diet and no myotonia. Studies of model membrane systems composed of phospholipid vesicles containing desmosterol, cholesterol, or both demonstrated that desmosterol increased membrane lipid fluidity relative to cholesterol, suggesting that in 20,25-diazacholesterol-induced myotonia, in which desmosterol accounts for 85% of the plasma sterol, the increased membrane fluidity previously observed in erythrocytes and sarcolemma in this animal model of human congenital myotonia may be due to desmosterol.

Topics: Animals; Azacosterol; Cholesterol, Dietary; Desmosterol; Disease Models, Animal; Erythrocyte Membrane; Liposomes; Male; Membrane Fluidity; Myotonia; Rats; Rats, Inbred Strains

Topics: Animals; Azacosterol; Cell Membrane; Cholesterol; Desmosterol; Kinetics; Male; Membrane Lipids; Muscles; Myotonia; Ouabain; Phosphorylation; Rats; Rats, Inbred Strains; Sarcolemma; Sodium-Potassium-Exchanging ATPase; Thermodynamics

In rats treated biweekly with 20,25-diazacholesterol (200 mg/kg orally), the desmosterol level in skeletal muscle sarcolemma increased progressively to about 80% of membrane sterol while total sterol levels remained constant. Following a single oral dose of 20,25-D, the kinetics of desmosterol accumulation and subsequent loss in sarcolemma were more rapid than in whole muscle homogenates. The anisotropy of diphenylhexatriene fluorescence and the calculated microviscosity of the probe's microenvironment decreased significantly with increasing desmosterol levels in a temperature-dependent manner, although fluorescent lifetimes were not altered. Fluorescent probes which localize in more superficial regions of the membrane detected no change. Studies with erythrocyte ghost membranes yielded results comparable to sarcolemma. Replacement of membrane yielded results comparable to sarcolemma. Replacement of membrane cholesterol with desmosterol reduced the local microviscosity of membrane cholesterol with desmosterol reduced the local microviscosity of the membrane hydrophobic region associated with phospholipid acyl chains and sterol side chains, but had little apparent effect on more superficial, polar regions. These observations can be correlated with the membrane location of the unsaturated side chain in desmosterol.

Topics: Animals; Azacosterol; Cell Membrane; Cholesterol; Desmosterol; Male; Membrane Lipids; Muscles; Myotonia; Rats; Rats, Inbred Strains; Sarcolemma; Viscosity

Topics: Action Potentials; Animals; Azacosterol; Chlorides; Cholesterol; Desmosterol; Electromyography; Male; Muscle Contraction; Muscles; Myotonia; Rats; Rats, Inbred Strains; Sarcolemma

Topics: Adenosine Triphosphatases; Animals; Aza Compounds; Calcium; Cholesterol; Desmosterol; Disease Models, Animal; Magnesium; Male; Muscles; Myotonia; Phosphatidylcholines; Phosphatidylethanolamines; Phosphatidylinositols; Phosphatidylserines; Potassium; Rats; Sodium; Sphingomyelins

20,25-Diazacholesterol, known to induce myotonia in skeletal muscle, also affects cardiac muscle as can be concluded from the development of cardiomegaly. At the same time (Na+, K+) ATPase of cardiac sarcolemmal membranes of the 20,25-diazacholesterol treated rats showed an increased activity as compared with control animals (91 percent and 46 percent stimulation respectively). The Ca++ stimulated ATPase showed the same tendency (96 percent and 64 percent stimulation). In the plasma of the treated rats creatine phosphokinase activity was found to be elevated whereas the amount of protein-bound iodine was decreased, a finding that is common in myotonic dystrophy.

Topics: Adenosine Triphosphatases; Animals; Aza Compounds; Biological Transport; Body Weight; Cardiomegaly; Cholesterol; Desmosterol; Female; Myocardium; Myotonia; Organ Size; Rats; Sarcolemma

Topics: Adenosine Triphosphatases; Animals; Anticholesteremic Agents; Cell Membrane; Cholesterol; Cholesterol, Dietary; Desmosterol; Electromyography; Erythrocytes; Muscles; Myotonia; Rats; Sterols

Topics: Adenosine Triphosphatases; Animals; Cholesterol; Desmosterol; Enzyme Activation; Erythrocytes; Male; Muscles; Myotonia; Potassium; Rats; Sodium; Time Factors

Desmosterol is found in various organs of rats that show signs of myotonia in their skeletal muscle as a result of treatment with 20.25-diazacholesterol. The amount of desmosterol depends on the time of treatment, and is different in different organs and different kinds of muscle. The increase in desmosterol is much lower and the rats do not show any signs of myotonia when fed a cholesterol rich diet in addition to treatment with 20.25-diazacholesterol. Treatment with triparanol also causes desmosterol accumulation but in these rats myotonia is rarely observed. Our results suggest that in the experimental animals myotonia becomes manifest when every second cholesterol molecule of the muscle cell membrane is replaced by desmosterol. This is easily achieved in animals fed with 20.25-diazacholesterol but rarely occurs with triparanol.

Topics: Animals; Azasteroids; Brain; Cholesterol; Desmosterol; Disease Models, Animal; Kidney; Male; Muscles; Myocardium; Myotonia; Organ Specificity; Rats; Triparanol

Myotonia induced in rats by 20,25-diazacholesterol is accompanied by accumulation of desmosterol in serum, fragmented sarcoplasmic reticulum, and sarcolemma. Activities of (Na(+),K(+))- and Ca(2+)-stimulated adenosine triphosphatases of the sarcolemma are increased, but not the Mg(2+)-stimulated adenosine triphosphatase. The altered sterol composition of the sarcolemma may cause this type of myotonia by decreasing the chloride conductance of the membrane.

Topics: Adenosine Triphosphatases; Animals; Aza Compounds; Cholesterol; Desmosterol; Female; Muscles; Myotonia; Rats; Sarcolemma; Sarcoplasmic Reticulum; Sterols

Topics: Adenosine Triphosphatases; Animals; Aza Compounds; Calcium; Cell Membrane; Cholesterol; Desmosterol; Enzyme Activation; Erythrocytes; Myotonia; Ouabain; Potassium; Rats; Sodium

Topics: Adenosine Triphosphatases; Animals; Aza Compounds; Cataract; Cell Membrane; Cholesterol; Chromatography, Gas; Desmosterol; Erythrocytes; Lipids; Magnesium; Male; Myotonia; Ouabain; Phospholipids; Potassium; Rats; Sodium

Topics: Androstenes; Animals; Anticholesteremic Agents; Brain; Cholesterol; Desmosterol; Diethylamines; Disease Models, Animal; Electroencephalography; Ketosteroids; Myotonia; Opossums; Seizures; Somatosensory Cortex