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  • Author or Editor: Esther M. Gallant x
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Abstract

Objective—To determine whether an alteration in calcium regulation by skeletal muscle sarcoplasmic reticulum, similar to known defects that cause malignant hyperthermia (MH), could be identified in membrane vesicles isolated from the muscles of Thoroughbreds with recurrent exertional rhabdomyolysis (RER).

Sample Population—Muscle biopsy specimens from 6 Thoroughbreds with RER and 6 healthy (control) horses.

Procedures—RER was diagnosed on the basis of a history of > 3 episodes of exertional rhabdomyolysis confirmed by increases in serum creatine kinase (CK) activity. Skeletal muscle membrane vesicles, prepared by differential centrifugation of muscle tissue homogenates obtained from the horses, were characterized for sarcoplasmic reticulum (SR) activities, including the Ca2+ release rate for the ryanodine receptor-Ca2+ release channel, [3H]ryanodine binding activities, and rate of SR Ca2+-ATPase activity and its activation by Ca2+.

Results—Time course of SR Ca2+-induced Ca2+ release and [3H]ryanodine binding to the ryanodine receptor after incubation with varying concentrations of ryanodine, caffeine, and ionized calcium did not differ between muscle membranes obtained from control and RER horses. Furthermore, the maximal rate of SR Ca2+-ATPase activity and its affinity for Ca2+ did not differ between muscle membranes from control horses and horses with RER.

Conclusions and Clinical Relevance—Despite clinical and physiologic similarities between RER and MH, we concluded that RER in Thoroughbreds does not resemble the SR ryanodine receptor defect responsible for MH and may represent a novel defect in muscle excitation-contraction coupling, calcium regulation, or contractility. (Am J Vet Res 2000;61:242–247)

Full access
in American Journal of Veterinary Research

Abstract

Objective

To determine whether increased sensitivity to pharmacologic agents was a general property of equine exertional myopathies, including polysaccharide storage myopathy (PSSM) in Quarter Horses.

Animals

5 adult Quarter Horses with exertional rhabdomyolysis and abnormal polysaccharide accumulation in skeletal muscle and 4 clinically normal adult Quarter or Quarter-type horses.

Procedures

Twitch time course measurements and contracture responses to various concentrations of caffeine and halothane for small bundles of intact external intercostal muscle fibers were measured in all horses.

Results

Caffeine contracture threshold of muscles from Quarter Horses with PSSM was not different from that of clinically normal horses (5 mM in both groups). Muscles from horses with PSSM and from clinically normal horses did not have contracture in response to up to 2% halothane.

Conclusions and Clinical Relevance

Results were in contrast to the increased sensitivity to caffeine and halothane for muscles from Thoroughbreds with recurrent exertional rhabdomyolysis (RER). Although clinical signs of muscular stiffness after exercise are similar between Quarter Horses with PSSM and Thoroughbreds with RER, these breeds appear to have 2 distinct myopathies with different pathophysiologic bases. Unlike RER in Thoroughbreds, PSSM in Quarter Horses does not appear to be accompanied by a defect in regulation of muscle contraction. (Am J Vet Res 1999;60:684–688)

Free access
in American Journal of Veterinary Research

Abstract

Objective—To determine whether there was genetic linkage between the recurrent exertional rhabdomyolysis (RER) trait in Thoroughbred horse pedigrees and DNA markers in genes (the sarcoplasmic reticulum calcium release channel [RYR1] gene, the sarcoplasmic reticulum calcium ATPase [ATP2A1] gene, and the transverse tubule dihydropyridine receptor-voltage sensor [CACNA1S] gene) that are important in myoplasmic calcium regulation.

Animals—34 horses in the University of Minnesota RER resource herd and 62 Thoroughbreds from 3 families of Thoroughbreds outside of the university in which RER-affected status was assigned after 2 or more episodes of ER had been observed.

Procedures—Microsatellite DNA markers from the RYR1, ATP2A1, and CACNA1S gene loci on equine chromosomes 10, 13, and 30 were identified. Genotypes were obtained for all horses in the 4 families affected by RER, and data were used to test for linkage of these 3 loci to the RER phenotype.

Results—Analysis of the RYR1, CACNA1S, and ATP2A1 microsatellites excluded a link between those markers and the RER trait.

Conclusions and Clinical Relevance—It is likely that the heritable alterations in muscle contractility that are characteristic of RER are caused by a gene that is not yet known to cause related muscle disease in other species.

Full access
in American Journal of Veterinary Research

Abstract

Objective

To determine whether abnormal regulation of muscle contraction similar to that associated with malignant hyperthemia (MH) was evident in intact external intercostal muscle cells from Thoroughbreds with recurrent exertional rhabdomyolysis (RER).

Animals

5 adult Thoroughbred horses with RER and 7 clinically normal adult Thoroughbred or mixed-breed horses.

Procedures

Twitch time course variables and contracture responses to various concentrations of potassium, caffeine, and halothane were measured in small bundles of intact external intercostal muscle cells from clinically normal horses and horses with RER.

Results

Threshold for significant contracture induced by potassium depolarization was lower for RER-affected muscles, compared with normal muscles, although the relationship between potassium concentration and membrane potential were not different. Thresholds for contracture induced by caffeine and halothane were also lower for RER-affected muscles, compared with normal muscles. Lower thresholds for caffeine- and halothane-induced contractures, as well as depolarization-elicited contractures, in RER-affected muscles suggest a defect in myoplasmic calcium regulation.

Conclusions and Clinical Relevance

Regulation of muscle contraction is abnormal in Thoroughbreds with RER. The specific defect may be attributable to abnormal intracellular calcium regulation. Knowledge of the specific defect involved in RER may lead to improved prevention and treatment of RER-affected horses. (Am J Vet Res 1999;60:992-999)

Free access
in American Journal of Veterinary Research

Abstract

Objective—To determine whether the basis for recurrent exertional rhabdomyolysis (RER) in Thoroughbreds lies in an alteration in the activation and regulation of the myofibrillar contractile apparatus by ionized calcium.

Animals—4 Thoroughbred mares with RER and 4 clinically normal (control) Thoroughbreds.

Procedure—Single chemically-skinned type-I (slowtwitch) and type-II (fast-twitch) muscle fibers were obtained from punch biopsy specimens, mounted to a force transducer, and the tensions that developed in response to a series of calcium concentrations were measured. In addition, myofibril preparations were isolated from muscle biopsy specimens and the maximal myofibrillar ATPase activity, as well as its sensitivity to ionized calcium, were measured.

Results—Equine type-I muscle fibers were more readily activated by calcium than were type-II muscle fibers. However, there was no difference between the type-II fibers of RER-affected and control horses in terms of calcium sensitivity of force production. There was also no difference between muscle myofibril preparations from RER-affected and control horses in calcium sensitivity of myofibrillar ATPase activity.

Conclusion and Clinical Relevance—An alteration in myofibrillar calcium sensitivity is not a basis for pathologic contracture development in muscles from RER-affected horses. Recurrent exertional rhabdomyolysis in Thoroughbreds may represent a novel heritable defect in the regulation of muscle excitation-contraction coupling or myoplasmic calcium concentration. (Am J Vet Res 2001;62:1647–1652)

Full access
in American Journal of Veterinary Research

Abstract

Objective—To determine whether alterations in myoplasmic calcium regulation can be identified in muscle cell cultures (myotubes) and intact muscle fiber bundles derived from Thoroughbreds affected with recurrent exertional rhabdomyolysis (RER).

Animals—6 related Thoroughbreds with RER and 8 clinically normal (control) Thoroughbred or crossbred horses.

Procedures—Myotube cell cultures were grown from satellite cells obtained from muscle biopsy specimens of RER-affected and control horses. Fura-2 fluorescence was used to measure resting myoplasmic calcium concentration as well as caffeine- and 4-chloro-m-cresol (4-CMC)-induced increases in myoplasmic calcium. In addition, intact intercostal muscle fiber bundles were prepared from both types of horses, and their sensitivities to caffeine- and 4-CMC-induced contractures were determined.

Results—Myotubes of RER-affected and control horses had identical resting myoplasmic calcium concentrations. Myotubes from RER-affected horses had significantly higher myoplasmic calcium concentrations than myotubes from control horses following the addition of ≥ 2mM caffeine; however, there was no difference in their response to 4-CMC (≥ 1mM). Caffeine contracture thresholds for RER and control intact muscle cell bundles (2 vs 10mM, respectively) were significantly different, but 4-CMC contracture thresholds of muscle bundles from RER-affected and control horses (500µM) did not differ.

Conclusions and Clinical Relevance—An increase in caffeine sensitivity of muscle cells derived from a family of related RER-affected horses was detected in vitro by use of cell culture with calcium imaging and by use of fiber bundle contractility techniques. An alteration in muscle cell calcium regulation is a primary factor in the cause of this heritable myopathy. (Am J Vet Res 2002;63:1724–1731)

Full access
in American Journal of Veterinary Research

Abstract

Objective—To develop a diagnostic test for recurrent exertional rhabdomyolysis (RER) in Thoroughbreds that relied on in vitro contracture of muscle biopsy specimens and determine whether the inheritance pattern of RER diagnosed on the basis of this contracture test was consistent with an autosomal dominant trait.

Design—Clinical trial.

Animals—8 adult horses with RER and 16 control adult horses for development of the contracture test; 23 foals for inheritance of RER.

Procedure—External intercostal muscle biopsy specimens from the 24 adult horses were tested for contracture in response to halothane and caffeine, and criteria for a positive test result were determined. These criteria were then applied to results for the 23 foals to determine whether they had RER. Simple segregation analysis was performed to determine whether results were consistent with a dominant pattern of inheritance.

Results—Results of the contracture test were positive for 5 of the 12 colts and 4 of the 11 fillies. Results of segregation analysis were consistent with an autosomal dominant pattern of inheritance. Two sires with RER produced colts with RER, supporting the hypothesis that RER had an autosomal, rather than an X-linked, inheritance pattern. In addition, in 1 instance, an unaffected colt was produced by 2 affected parents, which was not consistent with a recessive mode of inheritance.

Conclusions and Clinical Relevance—Although the expression of the RER trait is influenced by sex, temperament, and diet, among other factors, results from the in vitro muscle contracture test and this breeding trial suggest that RER in Thoroughbreds can be modeled as a genetic trait with an autosomal dominant pattern of inheritance. ( J Am Vet Med Assoc 2005;227:762–767)

Full access
in Journal of the American Veterinary Medical Association