Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 15 Skeletal Muscle Function
and goats ( Bryant and Conte-Camerino, 1991 ; Vite et al. ,
1998 ). Histopathological changes in skeletal muscle are
usually minimal and nonspecific. The canine mutation
results in a threonine residue in the D5 transmembrane
segment with methionine ( Bhalerao et al. , 2002 ; Rhodes
et al. , 1999 ). Functional characterization of the mutation
demonstrates a profound effect on the voltage dependence
of activation such that mutant channels have a greatly
reduced open probability at voltages near the resting membrane
potential of skeletal muscle.
Myotonic dystrophy differs from congenital myotonia
in that it is progressive and variably involves a variety of
other systems (e.g., smooth muscle of hollow organs, heart,
brain and peripheral nerves, endocrine glands, eyes, skeletal
system, and integument) ( Harper and Monckton, 2004 ).
In humans, this disorder results from repeat expansion in
the untranslated region of the DMPK (dystrophic myotonia
protein kinase) gene ( Davis et al. , 1997 ) or a specific
zinc-finger gene ( Liquori et al. , 2001 ). Part of the unique
molecular pathogenesis of these repeat expansions appears
to involve production of toxic RNA repeats, which lead to
aberrant splicing of many other proteins. The systemic features
are most helpful in differentiating between myotonia
congenita and myotonic dystrophy in addition to consistent
histopathological features, which include increased central
nuclei, ringed fibers, sarcoplasmic masses, and type 1 fiber
atrophy. Myotonic disorders have been described in horses
that have similar histopathological and electromyographic
abnormalities ( Hegreberg and Reed, 1990 ; Montagna
et al. , 2001 ; Reed et al. , 1988 ). The precise molecular
mechanism for myotonic dystrophy in horses is unknown.
4 . Calcium Release Channels of the Sarcoplasmic
Reticulum and Malignant Hyperthermia
Malignant hyperthermia (MH) is an inherited pharmacogenetic
disorder of humans, swine, dogs, and horses. When
exposed to halogenated anesthetics or succinylcholine, genetically
MH susceptible (MHS) individuals exhibit tachycardia,
hyperthermia, elevated carbon dioxide production, and
death if the anesthetic is not discontinued. Metabolic acidosis
and muscle rigidity are severe in both swine and humans,
whereas in dogs metabolic acidosis is usually moderate and
muscle rigidity is minimal ( Nelson, 1991 ). In swine, stresses
such as fighting, transport, and exercise also trigger its onset.
During an attack, serum CK and AST enzyme activities are
markedly elevated because of extensive myonecrosis. MH
is inherited as an autosomal recessive gene in swine ( Fujii
et al. , 1991 ) but as an autosomal dominant gene in humans,
horses, and dogs ( Monnier et al. , 2005 ; Roberts et al. , 2001 ;
Aleman et al. , 2004). Genetic mapping of the MH locus in
pigs and humans placed it in the vicinity of the RYR1 gene,
which encodes the sarcoplasmic reticulum ryanodine receptor
(calcium release channel). In addition, many biochemical
and physiological measurements implicated this very large
protein as the site of the defect in both pigs and humans
( Mickelson and Louis, 1996 ). Base pair sequence defects
in the RYR1 have now been identified for pigs ( Fujii et al. ,
1991 ), humans ( Treves et al. , 2005 ), dogs (Roberts et al. ,
2001 ), and horses ( Aleman et al. , 2004 ).
The clinical signs of increased muscle metabolism
and muscle contracture are likely due to the effects of the
RYR1 mutation on the gating properties of this channel.
Many studies have shown that calcium release channels
in MHS have a greater open probability, allowing greater
rates of calcium efflux from the SR terminal cisternae into
the myoplasm, which is exacerbated by the MH triggering
agents ( Mickelson and Louis, 1996 ). The SR calcium
ATPase is unable to resequester the calcium back into
the SR lumen fast enough, and the myoplasmic calcium
concentration rises. The resulting MH episode is due to
calcium stimulation of phosphorylase, myofilament contractile
activity, and the resultant activation of aerobic and
anaerobic metabolism to fuel the contraction.
No specific histopathological features are present in
most susceptible individuals apart from nonspecific findings
of central nuclei. One specific form of MH seen in
children with muscle weakness produces central core disease.
Biopsies in these cases are characterized by lack of
mitochondrial and myofibrillar staining in discrete areas of
type I fibers ( Treves et al. , 2005 ).
Molecular genetic testing for the specific mutations in
RYR1 provides the most specific means of testing swine,
dogs, and horses and has largely replaced standardized in
vitro contracture tests.
B . Cytoskeletal Dystrophin Deficiency and
Muscular Dystrophy
Duchenne muscular dystrophy is an X-linked recessive
disorder of skeletal muscle in humans, dogs, and
cats ( Kornegay et al. , 1988 ; Shelton, 2004 ; Shelton and
Engvall, 2002, 2005 ). The disorder is due to a deficiency
of a subsarcolemmal cytoskeletal protein dystrophin that
participates in the attachment of myofibrils to the sarcolemma
( Hoffman et al. , 1987 ). Dystrophin in concert with
a transmembrane protein complex (dystrophin-associated
protein) is believed to provide stability to the sarcolemma.
The deficiency of dystrophin presumably creates structural
instability of the sarcolemma allowing uncontrolled focal
ingress of extracellular fluid components such as calcium.
A number of mutations of the dystrophin gene have
been identified. Golden retrievers have a splice site mutation
in the dystrophin gene, which causes a premature termination
codon in exon 8 and a peptide that is 5% the size
of normal dystrophin ( Sharp et al. , 1992 ). The mutation in
the cat has not been identified.
The expression of the disease varies among species but
may be characterized as a progressive degenerative disorder