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C J Duncan

Publications and source records attributed to C J Duncan.

At least 109 records · Page 6Linked to original sources
PubMed1978

Role of intracellular calcium in promoting muscle damage: a strategy for controlling the dystrophic condition.

It is suggested that various muscle diseases and examples of experimentally-induced muscle damage arise because of a high calcium level in the myoplasm. When [Ca2+]i is raised experimentally in amphibian or mammaliam muscle by treatment with A23187 or caffeine, myofilament degradation follows quickly. Such a rapid action suggests the involvement of a sequence of proteolytic activity that is stimulated by a rise in [Ca2+]i. Ca2+ might either trigger protease activity directly or indirectly, or promote the release of lysosomal enzymes. A high [Ca2+]i in dystrophic muscle is believed to be the resultant of a sequence of events that is summarized in the figure. Suggestions are presented for different ways in which the steady-state position of [Ca2+]i might ultimately be controlled for the clinical amelioration of some dystrophic conditions.

Animals↗
PubMed1978

The action of caffeine in promoting ultrastructural damage in frog skeletal muscle fibres. Evidence for the involvement of the calcium-induced release of calcium from the sarcoplasmic reticulum.

1. Caffeine at concentrations above 5 mM was shown to cause rapidly extensive ultrastructural damage to the myofibrils of frog skeletal muscle. 2. The effect was promoted at lower temperatures, whereas the myofibrils were protected by prior exposure to procaine. 3. It is argued that caffeine causes a Ca2+-induced release of Ca2+ (the CROC) from the S.R. and that the consequent rise in [Ca2+]i promotes the ultrastructural damage observed. 4. Myofibril digradation is also produced by treatment of the muscle with the divalent cation ionophore A23187; this effect is not protected by either procaine or Dantrolene sodium. 5. It is suggested that A23187 causes the release of Ca2+ from the S.R. by a mechanism that differs from both excitation and the CROC; the resultant rise in [Ca2+]i again causes myofibril degradation. 6. The ways in which a marked rise in [Ca2+]i could cause muscle damage and the possible relevance of these findings to the sequence of events in the development of myopathies of human skeletal muscle are discussed.

Animals↗
PubMed1978

The use of A23187 to demonstrate the role of intracellular calcium in causing ultrastructural damage in mammalian muscle.

Electron micrographs show that treatment of mouse diaphragm with the divalent cation ionophore A23187 causes major ultrastructural damage in the muscle. During the first 30 min of exposure to A23187, the mitochondria swell markedly but after 40 min they undergo further ultrastructural changes and a rapid dissolution of the myofilaments is also seen at this time. In place only remnants of the filaments remain. It is suggested that the ionophore causes the release of Ca2+ from the sarcoplasmic reticulum which, initially, is taken up by the mitochondria, causing then to swell; after 40 min the mitochondria release the accumulated Ca2+. It is argued that the rise in [ca2+]i stimulates neutral proteases in the myoplasm and that the sequence of events following ionophore treatment may act as a model for the involvement of Ca2+ in various myopathies. We have shown previously (29) that treatment of the cutaneous pectoris muscle of the frog with the divalent cation ionophore A23187 has three major effects: (i) The membrane potential (Em) is depolarized, an action that is found only when the Ca2+ -concentration of the bathing saline is very low. (ii) It causes an increase in resting tension and the development of contraction. This effect is found at both normal (1.8 mM) and low values of [Ca2+]o and is, therefore, independent of Ca2+ entry and of changes in Em. The ionophore is believed to act primarily by releasing Ca2+ from intracellular stores. (iii) It causes major ultrastructural damage to the muscle filaments. The evidence suggests that A23187 acts at the sarcoplasmic reticulum of frog muscle, causing the release of stored Ca2+ , and the consequent rise in [Ca2+]i stimulates a Ca2+ -activated protease which is responsible for the myofilament degradation. A calcium-activated factor has been isolated from rabbit skeletal muscle; this enzyme operates at neutral pH, hydrolyses denatured casein, and specifically removes the Z-lines and alpha-actinin from skeletal muscle (24). A Ca2+ -activated protease with a pH optimum of 7.5 has also been purified from porcine skeletal muscle; it removes Z-discs, degrades troponin and tropomyosin and partly degrades M lines, and it has been suggested that it may have a physiological role in the disassembly of intact myofibrils during the metabolic turnover of myofibrillar proteins (6, 7). This protases is not localized in membrane-bounded sub-cellular particles, but is believed to be in direct contact with the cytoplasm (26). These findings are of particular interest in thelight of recent suggestions that the cellular necrosis observed in various muscle diseases is a consequence of an increased net influx of calcium into cells which causes, in turn, calcium overloading of the muscle mitochondria (34, 35). We have, therefore, extended our previous studies with frog muscle by the examination of the action of A23187 on the mammalian skeletal muscle of mouse diaphragm...

Animals↗
PubMed1977

Ultrastructural changes in muscle mitochondria in situ, including the apparent development of internal septa, associated with the uptake and release of calcium.

Treatment of mammalian muscle with the divalent cation ionophore A23187 causes the release of Ca2+ from the sarcoplasmic reticulum and allows the ultrastructural changes of the mitochondria during Ca2+-uptake to be demonstrated in situ. Electron micrographs reveal that the mitochondria swell dramatically during uptake, before contracting again when the accumulated Ca2+ is released once more into the cytoplasm. When maximally swollen, the mitochondria are apparently subdivided and internal "septa" are formed. The ultrastructural details concerning these internal membranous structures are shown in detail and their significance is discussed.

Animals↗
PubMed1977

A note on the evolution of the transducer mechanism of the vertebrate retinal rod.

The Ca2+-gating mechanism that is the key component of membrane excitability in paramecium has recently been localized on the cilia of this animal. Such a finding shows how the change in Ca2+ permeability (which is the probable consequence of the photoisomerization of rhodopsin) of the discs of the outer segments of the retinal rods could have evolved.

Animals↗
PubMed1977

The action of ouabain in promoting the release of catecholamines.

It is suggested that ouabain promotes catecholamine release by causing a rise in intracellular Na+ which, in turn, causes an elevated steady-state level of intracellular Ca2+. It is suggested that the Na+-K+-ATPase is not directly involved in exocytosis at either adrenergic or cholinergic synapses.

Adenosine Triphosphatases↗
PubMed1977

Interacting effects of temperature and extracellular calcium on the spontaneous release of transmitter at the frog neuromuscular junction.

1. Temperature has a characteristic effect on the frequency of m.e.p.p.s at the frog neuromuscular junction; the spontaneous release of transmitter is not affected by temperature changes below 10 degrees C whereas the system is highly temperature-sensitive above 20 degrees C.2. A very similar result is obtained when the experiment is repeated in saline containing Ca(2+) buffered at 5 x 10(-7)M, suggesting that it is unlikely that the major action of temperature is to cause an increase in Ca(2+) influx.3. It is suggested that the main effect of temperature at the presynaptic terminals is a modification of [Ca(2+)](i) by an action on intracellular Ca(2+) stores.4. The interacting effects of theophylline and the divalent cation ionophore A23187 on m.e.p.p. frequency suggest that intracellular Ca(2+) stores, in addition to the mitochondria, may well be of importance in controlling [Ca(2+)](i).5. Changes in [Ca(2+)](o) produce a modification of m.e.p.p. frequency, but the details of the response are dependent on temperature. The spontaneous release of transmitter is most sensitive to an increase in [Ca(2+)](o) at 23 degrees C, whereas the greater effect is found at 13 degrees C when [Ca(2+)](o) is lowered.6. It is suggested (i) that m.e.p.p. frequency is primarily determined by [Ca(2+)](i) at the presynaptic terminals, (ii) that the presynaptic terminals are normally able to maintain [Ca(2+)](i) almost constant in spite of increases in Ca influx associated with ionophore treatment or with a rise in [Ca(2+)](o). However, if the steady-state position of [Ca(2+)](i) is previously raised by an increased efflux from intracellular stores (produced by elevated temperature or theophylline pre-treatment), increased influx causes a rise in both [Ca(2+)](i) and in m.e.p.p. frequency.

Animals↗
PubMed1976

The effect of the ionophore A23187 on the ultrastructure and electrophysiological properties of frog skeletal muscle.

The divalent cation ionophore A23187 has three major effects on the thin cutaneous pectoris muscle of frog: (1) The membrane potential is depolarized, an action that is found only when the [Ca2+] of the bathing saline is very low.(2) It causes an increase in resting tension and the development of contraction. This action is produced at both normal and low values of [Ca2+]o and is, therefore, independent of Ca2+ entry and of changes in Em. The ionophore is believed to act primarily by releasing Ca2+ from intracellular stores. (3) It causes major ultrastructural damage to the muscle filaments. It is believed that this damage is the result of the action of A23187 on the sarcoplasmic reticulum and the elevation of [Ca2+]i and we suggest that the action of thisionophore may serve as a useful model for the study of certain myopathies.

Animals↗
PubMed1976

Dantrolene and the neuromuscular junction: evidence for intracellular calcium stores.

Dantrolene sodium (DaNa) markedly depressed the frequency of spontaneous miniature potentials at the frog neuromuscular junction. Its action is still observed at low [Ca2+]o and is little affected by temperature; its effect is not readily reversible. Theophylline antagonises the action of DaNa. DaNa prevents the stimulatory effect of the ionophore A23187 at 25 degrees C, but is ineffective in antagonising the action of X537A. DaNa and theophylline do not affect the functioning and integrity of mitochondria in vitro and it is suggested that DaNa acts at intracellular Ca2+ stores (other than the mitochondria) in the presynaptic terminals.

Animals↗