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Some biological effects of experimentally induced inhibition of oxidative phosphorylation in rat skeletal muscle

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Byrne, Edward (1984) Some biological effects of experimentally induced inhibition of oxidative phosphorylation in rat skeletal muscle. PhD thesis, University of Tasmania.

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Abstract

I) Selective defects in the mitochondrial respiratory
chain and in the coupling of respiration to phosphorylation
underlie weakness and exercise intolerance in certain
mliopatbies (see Carafoli and Roman 1980: Morgan-Hughes
1981). In this study specific defects in these pathways
have been reproduced in the rat using the respiratory chain
inhibitors diphenyleneiodonium and antimycin A and the
uncoupling agent dinitrophenol. These disease models
have been characterised using electrophysiological, biochemical
and morphological techniques and the findings
have furthered the understanding of the pathophysiology
of human mitochondrial myopathies. Mitochondrial inhibitors
were either injected intraarterially into anaesthetised
animals or given by repeated daily subcutaneous injection.
Isometric twitch tension and compound muscle action
potentials evoked by nerve or by direct muscle stimulation
were recorded from the gastrocnemius muscle in vivo during
various stimulus patterns. The gastrocnemius muscle was
either freeze clamped for metabolite assay or fixed for
histological study at various times after injection. In
a second series of experiments, the biochemical changes
were followed using 31 phosphorous nuclear magnetic resonance.
The effects of acute ischaemia and blocked glycolysis
were also studied in vivo for comparative purposes.
In vitro intracellular recordings were made from individual
soleus muscle fibres in separate experiments. 2) Intra-arterial injection of dinitrophenol resulted
in irreversible failure of twitch tension and loss of
muscle action potential associated with the development
of an electrically silent contracture. In vitro intracellular
recordings from soleus muscle fibres demonstrated
a progressive broadening of the action potential, with a
fall in amplitude and eventual failure of propogation.
This was associated with a small reduction in resting
potential. Force failure was accompanied by a rapid depletion
of phosphocreatine and adenosine triphospbate (ATP)
accumulation of inosine monophosphate (IMP) and a fall in
intramuscular pH with lactate accumulation. Enlarged mitochondria
with whorled, fractured or lysed cristae, myelin
figures, and intracristal linear inclusions were seen 60
minutes after infusion.
3) Intra-arterial or repeated subcutaneous injection
of diphenyleneiodonium which is known to inhibit NADH
ubiquinone reductase resulted in a progressive fall in
twitch tension with 1 and 5c/sec stimulation patterns
accompanied by a marked prolongation of relaxation time.
Failure of muscle excitation paralleled force failure.
Contracture as determined by a rise in resting tension ;
developed inconsistently as a late finding only in animals
given large doses of DPI. Considerable recovery of force
generation occurred with rest. After a single injection
a pattern of rapid fatiguability followed by a Partial
recovery was established with repeated bursts of 5c/sec stimulation. With DPI, force failure was associated
with depletion of PCr but ATP levels were similar to
those in control muscle exposed ,1 to the same stimulus,
pattern. A massive rise in muscle lactate concentrations
with light work was seen in animals given subcutaneous
DPI.
With DPI mitochondrial changes were minor after
intra-arterial infusion. In animals given repeated
subcutaneous injections, the changes were more marked
and resembled those'seen more acutely_ after dinitrophenol.

4) Abnormal force failure followed injection of antimycin
A, but systemic toxicity limited the usefulness of
this agent and only 5 experiments were undertaken. 5) Intra-arterial infusion of the glycolytic inhibitor
iodoacetate resulted in a rapid failure of twitch tension
and muscle exictability, associated with contracture.
Severe ATP depletion and IMP accumulation were found in
contractured_muscle.

Item Type: Thesis (PhD)
Keywords: Muscles, Mitochondria, Tissue respiration
Copyright Holders: The Author
Copyright Information:

Copyright 1984 the Author - The University is continuing to endeavour to trace the copyright
owner(s) and in the meantime this item has been reproduced here in good faith. We
would be pleased to hear from the copyright owner(s).

Additional Information:

Thesis (M.D.) - University of Tasmania, 1984. Bibliography: leaves 265-289

Date Deposited: 25 Nov 2014 00:43
Last Modified: 04 Jul 2017 05:08
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