Richard J. Piercy's research while affiliated with Royal Veterinary College and other places
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Publications (155)
Background
Duchenne muscular dystrophy is a X-linked disease characterized by severe and progressive muscle weakness, alongside cognitive impairment and a range of neurobehavioral disorders secondary to brain dystrophin deficiency. Duchenne muscular dystrophy patients have reduced cerebral gray matter and altered white matter ultrastructure (detect...
Dystrophin is essential for muscle health: its sarcolemmal absence causes the fatal, X-linked condition, Duchenne muscular dystrophy (DMD). However, its normal, spatial organization remains poorly understood, which hinders the interpretation of efficacy of its therapeutic restoration. Using female reporter mice heterozygous for fluorescently tagged...
Duchenne muscular dystrophy (DMD) is a fatal muscle-wasting disease, caused by mutations in the dystrophin gene, characterised by cycles of muscle degeneration, inflammation and regeneration. Recently, there has been renewed interest specifically in drugs that ameliorate muscle inflammation in DMD patients. The DE50-MD dog is a model of DMD that cl...
Background : Animal models of Duchenne muscular dystrophy (DMD) are essential to study disease progression and assess efficacy of therapeutic intervention, however dystrophic mice fail to display a clinically relevant phenotype, limiting translational utility. Dystrophin-deficient dogs exhibit disease similar to humans, making them increasingly imp...
Background : Progression through mammalian embryogenesis involves many interacting cell types and multiple differentiating cell lineages. Quantitative polymerase chain reaction (qPCR) analysis of gene expression in the developing embryo is a valuable tool for deciphering these processes, but normalisation to stably-expressed reference genes is esse...
Morphological study of the neuromuscular junction (NMJ), a specialised peripheral synapse formed between a lower motor neuron and skeletal muscle fibre, has significantly contributed to the understanding of synaptic biology and neuromuscular disease pathogenesis. Rodent NMJs are readily accessible, and research into conditions such as amyotrophic l...
The aetiology and pathophysiology of many diseases of the motor unit remain poorly understood and the role of the neuromuscular junction (NMJ) in this group of disorders is particularly overlooked, especially in humans, when these diseases are comparatively rare. However, elucidating the development, function and degeneration of the NMJ is essentia...
New Mendelian genetic conditions, which adversely affect livestock, arise all the time. To manage them effectively, some methods need to be devised that are quick and accurate. Until recently, finding the causal genomic site of a new autosomal recessive genetic disease has required a two-stage approach using single-nucleotide polymorphism (SNP) chi...
Background: Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease caused by mutations in the dystrophin gene. Due to their phenotypic similarity to human patients, large animal models are invaluable tools for pre-clinical trials. The DE50-MD dog is a relatively new model of DMD, and carries a therapeutically-tractable mutation lying w...
Introduction Fibrosis is a key feature of many chronic myopathic disorders, such as in the muscle-wasting condition, Duchenne muscular dystrophy. Fibrosis disrupts skeletal muscle architecture, limits muscle function, impairs regeneration and might reduce efficacy of therapeutic interventions: quantifying muscle fibrosis is thus of key value in mon...
Neurological disorders are prevalent in horses, but their study is challenging due to anatomic constraints and the large body size; very few host‐specific in vitro models have been established to study these types of diseases, particularly from adult donor tissue. Here we report the generation of primary neuronal dorsal root ganglia (DRG) cultures...
Duchenne muscular dystrophy (DMD), a fatal musculoskeletal disorder, is associated with neurodevelopmental disorders and cognitive impairment caused by brain dystrophin deficiency. Dog models of DMD represent key translational tools to study dystrophin biology and to develop novel therapeutics. However, characterization of dystrophin expression and...
Background: Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease caused by mutations in the dystrophin gene. Due to their phenotypic similarity to human patients, large animal models are invaluable tools for pre-clinical trials. The DE50-MD dog is a relatively new model of DMD, and carries a therapeutically-tractable mutation lying w...
Background : Progression through mammalian embryogenesis involves many interacting cell types and multiple differentiating cell lineages. Quantitative polymerase chain reaction (qPCR) analysis of gene expression in the developing embryo is a valuable tool for deciphering these processes, but normalisation to stably-expressed reference genes is esse...
The DE50-MD canine model of Duchenne Muscular Dystrophy (DMD) has a dystrophin gene splice site mutation causing deletion of exon 50, an out-of-frame transcript and absence of dystrophin expression in striated muscles. We hypothesised that the musculoskeletal phenotype of DE50-MD dogs could be detected using Magnetic Resonance Imaging (MRI), that i...
Abstract Horse racing is a popular and financially important industry worldwide and researchers and horse owners are interested in genetic and training influences that maximise athletic performance. An association has been found between the presence of a short interspersed nuclear element (SINE) mutation in the myostatin (MSTN) gene promoter and op...
Background
Hypoglycin A (HGA) intoxication after ingestion of Acer spp. tree material has never been confirmed in domesticated ruminants despite their similar grazing habitats.
Objectives
To investigate whether sheep have low HGA bioavailability caused by rumen HGA breakdown.
Animals
Stomach and rumen fluid samples from 5 adult horses and 5 adult...
Horse racing is a popular and financially important industry worldwide and researchers and horse owners are interested in genetic and training influences that maximise athletic performance. An association has been found between the presence of a short interspersed nuclear element (SINE) mutation in the myostatin ( MSTN ) gene promoter and optimal r...
Background:
Horses are affected by various peripheral nerve disorders but defining their aetiology and pathophysiology is hampered by limited understanding of associated morphological and pathological changes and involvement of specific axonal types.
Objectives:
To investigate the hypothesis that selected antibody markers, used in conjunction wi...
Mammalian embryogenesis is an intricate, tightly orchestrated process. Progression from zygote through somitogenesis and on to organogenesis and maturity involves many interacting cell types and multiple differentiating cell lineages. Quantitative PCR analysis of gene expression in the developing embryo is a valuable tool for deciphering these inte...
Dystrophin plays a vital role in maintaining muscle health, yet low mRNA expression, lengthy transcription time and the limitations of traditional in-situ hybridization (ISH) methodologies mean that the dynamics of dystrophin transcription remain poorly understood. RNAscope is highly sensitive ISH method that can be multiplexed, allowing detection...
Background: The dystrophin gene has multiple isoforms: full-length dystrophin (dp427) is principally known for its expression in skeletal and cardiac muscle, but is also expressed in the brain, and several internal promoters give rise to shorter, N-terminally truncated isoforms with wider tissue expression patterns (dp260 in the retina, dp140 in th...
Background:
Measurement of hypoglycin A (HGA) and its toxic metabolite, methylenecyclopropylacetic acid (MCPA), in equine serum confirms a diagnosis of atypical myopathy (AM), a pasture-associated toxic rhabdomyolysis with high mortality linked to the ingestion of Acer trees plant material. Supportive diagnostic tests include plasma acyl-carnitine...
Background: The dystrophin gene has multiple isoforms: full-length dystrophin (dp427) is principally known for its expression in skeletal and cardiac muscle, but is also expressed in the brain, and several internal promoters give rise to shorter, N-terminally truncated isoforms with wider tissue expression patterns (dp260 in the retina, dp140 in th...
A glutamic acid to lysine (E40K) residue substitution in superoxide dismutase 1 (SOD1) is associated with canine degenerative myelopathy: the only naturally occurring large animal model of amyotrophic lateral sclerosis (ALS). The E40 residue is highly conserved across mammals, except the horse, which naturally carries the (dog mutant) K40 residue....
Dystrophin plays a vital role in maintaining muscle health, yet low mRNA expression, lengthy transcription time and the limitations of traditional in-situ hybridization (ISH) methodologies mean that the dynamics of dystrophin transcription remain poorly understood. RNAscope is highly sensitive ISH method that can be multiplexed, allowing detection...
Introduction:
Equine recurrent laryngeal neuropathy (RLN) is a naturally occurring model of length-dependent axonopathy characterised by asymmetrical degeneration of recurrent laryngeal nerve axons (RLn). Distal RLn degeneration is marked, however it is unclear whether degeneration extends to include cell bodies (consistent with a neuronopathy)....
AIMS
To investigate the effect of the transverse arytenoid ligament (TAL) on abduction of the arytenoid cartilage when performing laryngoplasty.
METHODS
Modified prosthetic laryngoplasty was performed on right and left sides of 13 cadaver larynges. Increasing force was sequentially applied to the left arytenoid cartilage at 3 N intervals from 0–24...
Active muscle performs various mechanical functions during locomotion: work output during shortening, work absorption when resisting (but not preventing) lengthening, and impulse (force-time integral) whenever there is active force. The energetic costs of these functions are important components in the energy budget during locomotion.
We investigat...
Several horse breeds have been specifically selected for the ability to exhibit alternative patterns of locomotion, or gaits. A premature stop codon in the gene DMRT3 is permissive for “gaitedness” across breeds. However, this mutation is nearly fixed in both American Standardbred trotters and pacers, which perform a diagonal and lateral gait, resp...
Introduction
Controversy exists over the effects of functional electrical stimulation (FES) on reinnervation. We hypothesized that intramuscular FES would not delay reinnervation after recurrent laryngeal nerve (RLn) axonotmesis.
Methods
RLn cryo‐injury and electrode implantation in ipsilateral posterior cricoarytenoid muscle (PCA) were performed...
The dorsal cricoarytenoid (DCA) muscles, are a fundamental component of the athletic horse’s respiratory system: as the sole abductors of the airways, they maintain the size of the rima glottis which is essential for enabling maximal air intake during intense exercise. Dysfunction of the DCA muscle leads to arytenoid collapse during exercise, resul...
Background
Several pasture management strategies have been proposed to avoid hypoglycin A (HGA) intoxication in horses, but their efficacy has never been investigated.
Objectives
To evaluate the effect of mowing and herbicidal spraying on HGA content of Sycamore seedlings and the presence of HGA in seeds and seedlings processed within haylage and...
Gene editing and muscular dystrophy
Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness and a shortened life span. The disease is caused by mutations that reduce or prevent expression of dystrophin, an essential structural protein in skeletal and heart muscle. The gene editing technology CRISPR-Cas9 can correct disease...
Hypoglycin A (HGA) toxicity, following ingestion of material from certain plants, is linked to an acquired multiple acyl-CoA dehydrogenase deficiency known as atypical myopathy, a commonly fatal form of equine rhabdomyolysis seen worldwide. Whilst some plants are known to contain this toxin, little is known about its function or the mechanisms that...
Atypical myopathy / seasonal pasture myopathy is a toxic rhabdomyolysis of horses linked to the ingestion of hypoglycin A (HGA) contained in seeds and seedlings of some Acer tree species. Although the toxic effect of HGA's metabolite, methylenecyclopropylacetic acid (MCPA), has been studied in several species, it remains unclear why animals (such a...
Recurrent Laryngeal Neuropathy (RLN) is a highly prevalent and predominantly left‐sided, degenerative disorder of the recurrent laryngeal nerves (RLn) of tall horses, that causes inspiratory stridor at exercise because of intrinsic laryngeal muscle paresis. The associated laryngeal dysfunction and exercise intolerance in athletic horses commonly le...
Background:
Dogs with dystrophin-deficient muscular dystrophy are valuable models of the equivalent human disease, Duchenne Muscular Dystrophy (DMD): unlike the mdx mouse, these animals present a disease severity and progression that closely matches that found in human patients. Canine models are however less thoroughly characterised than the esta...
This Chapter describes how muscular pathology can lead to neck, back and pelvic pathology. The Chapter describes how to diagnose a muscle disorder using diagnostic procedures including biochemistry, DNA testing and biopsy and the use of diagnostic imaging techniques such as ultrasound, scintigraphy and EMG. Specific examples of muscle disorders, su...
doi.org/10.1111/jvim.15044
Atypical myopathy in horses can be caused by consumption of seedlings of Acer pseudoplatanus (sycamore) trees, which are widespread in horse pastures in Europe. However, optimal pasture management to avoid seedlings ingestion is unclear. Here we evaluated the effect of mowing and herbicidal spraying on hypoglycin A (HGA)...
Background:
Agreement amongst experienced clinicians is poor when assessing presence and severity of ataxia, especially when signs are mild. Consequently, objective gait measurements might be beneficial for assessment of horses with neurological diseases.
Objectives:
To assess diagnostic criteria using motion capture to measure variability of sp...
Background:
Equine atypical myopathy (AM) is a toxic rhabdomyolysis associated with ingestion of hypoglycin A, derived typically in Europe, from Acer pseudoplatanus tree. Despite the wide distribution of this tree species in the UK, the number of cases reported annually varies, and there has been an apparent increase in prevalence in recent years....
Dystrophin is a key cytoskeletal protein coded by the Duchenne muscular dystrophy (DMD) gene located on the X-chromosome. Truncating mutations in the DMD gene cause loss of dystrophin and the classical DMD clinical
syndrome. Spontaneous DMD gene mutations and associated phenotypes occur in several other species. The
mdx mouse model and the golden r...
Mutations in HACD1/PTPLA cause recessive congenital myopathies in humans and dogs. Hydroxyacyl-coA dehydratases are required for elongation of very long chain fatty acids, and HACD1 has a role in early myogenesis, but the functions of this striated muscle-specific enzyme in more differentiated skeletal muscle remain unknown. Canine HACD1 deficiency...
Although horses are affected by cranial nerve disease, our understanding of these structures' imaging anatomy is limited, and the optimal modality for imaging of each of these nerves is unclear. The aim of this study was to describe the imaging appearance of the equine cranial nerves on high-resolution 1.5T magnetic resonance imaging (MRI) and comp...
Background:
Equine type 1 polysaccharide storage myopathy (PSSM1) is associated with a missense mutation (R309H) in the glycogen synthase (GYS1) gene, enhanced glycogen synthase (GS) activity and excessive glycogen and amylopectate inclusions in muscle.
Methods:
Equine muscle biochemical and recombinant enzyme kinetic assays in vitro and homolog...
Recurrent exertional rhabdomyolysis (RER) in Thoroughbred and Standardbred racehorses is characterized by episodes of muscle rigidity and cell damage that often recur upon strenuous exercise. The objective was to evaluate the importance of genetic factors in RER by obtaining an unbiased estimate of heritability in cohorts of unrelated Thoroughbred...
Rhabdomyolysis (RM) may result from gene-environment interactions (1). Mutations in RYR1 lead to various neuromuscular phenotypes including malignant hyperthermia susceptibility and RM (2, 3). Preventive measures specifically aimed at RYR1-related RM mainly consist of avoidance of known triggers such as exercising in hot environments and untreated...
A yearling Thoroughbred colt was presented for investigation of neck stiffness and episodes of intermittent neck pain without neurological signs. Osteochondrosis (OCD) of the cervical articular process joints (APJs) was diagnosed with the aid of radiography and computed tomography. An articular osteochondral fragment of the left fourth caudal cervi...
Many North American Standardbreds race at the pace, an alternative two-beat gait characterized by ipsilateral limb movement. Modern breeding distinctly separates pacing lines from trotting, although ~20% of the offspring of trotter stallions race as pacers. A recently described functional mutation in DMRT3 (an isoform of the doublesex and mab-3 rel...
One of the 172 UK cases of equine atypical myopathy (EAM) reported to the Atypical Myopathy Alert Group (AMAG) in 2014 was that of a five-month old male Przewalski horse (Equus ferus przewalskii), resident at ZSL Whipsnade Zoo, UK. The foal presented initially with sudden-onset and repeated stretching of the neck as if dysphagic, with progressive w...
Bilateral vocal fold paralysis (BVCP) is a life-threatening condition that follows injury to the Recurrent Laryngeal nerve (RLn) and denervation of the intrinsic laryngeal musculature. Functional electrical stimulation (FES) enables restoration and control of a wide variety of motor functions impaired by lower motor neuron lesions. Here we evaluate...
A unilateral neurectomy model was used to study the relationship between histologic and ultrasonographic tissue characteristics during muscle atrophy over time.
In vivo experimental study in equine model (n=28). Mean pixel intensity of ultrasonographic images was measured, a muscle appearance grade was assigned weekly, and muscles were harvested fr...
The reduced diameter of skeletal myofibres is a hallmark of several congenital myopathies, yet the underlying cellular and molecular mechanisms remain elusive. In this study, we investigate the role of HACD1/PTPLA, which is involved in the elongation of the very long chain fatty acids, in muscle fibre formation. In humans and dogs, HACD1 deficiency...
OBJECTIVE To produce a clonal equine myoblast cell line that retains the ability to divide for multiple passages and differentiate into multinucleated myotubes during specific conditions.
SAMPLE Cultured primary equine skeletal muscle-derived cells from a healthy Thoroughbred.
PROCEDURES Cell cultures were transfected by electroporation with a plas...
Equine cervical osteoarthritis is a common disease known to contribute to both neck pain and cervical vertebral compressive myelopathy. There are no published studies demonstrating the usefulness of latero-oblique radiography as a diagnostic tool for cervical osteoarthritis. To determine the sensitivity, specificity and positive and negative predic...
Measurement of incorporation of stable isotope-containing amino acids into muscle is the gold-standard technique for measuring muscle protein synthesis (MPS), but its use in horses has not been evaluated. 1) To establish a technique for measuring MPS in vivo in the horse using a labelled amino acid tracer and 2) to determine basal MPS in the horse...
Advanced imaging modalities enable assessment of the equine skull and brain. Horses are susceptible to neurological dysfunction of the cranial nerves; however, our understanding of these structures’ imaging anatomy is limited. Magnetic resonance imaging (MRI) will be superior to computed tomography (CT) for the identification of cranial nerves, but...
Recurrent laryngeal neuropathy (RLN) is a common equine distal axonopathy associated with neurogenic atrophy of intrinsic laryngeal muscles (particularly the left) causing laryngeal paresis and poor performance. An objective, reliable method of assessing changes in structure that correlates with laryngeal muscle function in vivo is necessary to det...
Reasons for performing studyThe pathogenesis of bilateral dynamic laryngeal collapse associated with poll flexion (DLC) of horses is unknown but might be associated with intrinsic laryngeal muscle weakness.Objectives
To investigate histopathological characteristics of the cricoarytenoideus dorsalis (CAD), the cricothyroideus (CT) and the cricoaryte...
Dysfunctional skeletal muscle calcium homeostasis plays a central role in the pathophysiology of several human and animal skeletal muscle disorders, in particular, genetic disorders associated with ryanodine receptor 1 (RYR1) mutations, such as malignant hyperthermia, central core disease, multiminicore disease and certain centronuclear myopathies....
