Clinical and histopathological features of myofibrillar myopathy in Warmblood horses

Abstract

Summary Background To report a novel exertional myopathy, myofibrillar myopathy (MFM) in Warmblood (WB) horses. Objectives To 1) describe the distinctive clinical and myopathic features of MFM in Warmblood horses and 2) investigate the potential inheritance of MFM in a Warmblood family. Study design Retrospective selection of MFM cases and prospective evaluation of a Warmblood family. Methods Retrospectively, muscle biopsies were selected from Warmblood horses diagnosed with MFM and clinical histories obtained (n = 10). Prospectively, muscle biopsies were obtained from controls (n = 8) and a three generation WB family (n = 11). Samples were assessed for histopathology [scored 0–3], fibre types, cytoskeletal and Z disc protein aggregates, electron microscopic alterations (EM) and muscle glycogen concentrations. Results Myofibrillar myopathy-affected cases experienced exercise intolerance, reluctance to go forward, stiffness and poorly localised lameness. Abnormal aggregates of the cytoskeletal protein desmin were found in up to 120 type 2a and a few type 2x myofibres of MFM cases. Desmin positive fibres did not stain for developmental myosin, α actinin or dystrophin. Scores for internalised myonuclei (score MFM 0.83 ± 0.67, controls 0.22 ± 0.45), anguloid atrophy (MFM 0.95 ± 0.55, controls 0.31 ± 0.37) and total myopathic scores (MFM 5.85 ± 2.10, controls 1.41 ± 2.17) were significantly higher in MFM cases vs. controls. Focal Z disc degeneration, myofibrillar disruption and accumulation of irregular granular material was evident in MFM cases. Muscle glycogen concentrations were similar between MFM cases and controls. In the Warmblood family, desmin positive aggregates were found in myofibres of the founding dam and in horses from two subsequent generations. Main limitations Restricted sample size due to limited availability of well phenotyped cases. Conclusions A distinctive and potentially heritable form of MFM exists in Warmblood horses that present with exercise intolerance and abnormal hindlimb gait. Muscle tissue is characterised by ectopic accumulation of desmin and Z disc and myofibrillar degeneration.

Proteome and transcriptome profiling of equine myofibrillar myopathy identifies diminished peroxiredoxin 6 and altered cysteine metabolic pathways

“…Lower tropomyosin (↓3.2 log 2 fold MFM) content in MFM muscle could be the result of protein oxidation or alternatively, could reflect a primary underlying disorder (30, 35, 36). Decreased tropomyosin content is known to occur in limb girdle muscular dystrophy 2A and hereditary inclusion body myositis (24), (55), which have different histopathologic appearances compared with MFM in horses (63, 64). Mutations in the Z-disc protein MYOZ2 can cause myofibrillar disarray and hypertrophic cardiomyopathy and gene expression of MYOZ2 was significantly decreased in resting MFM vs. control horses (45).…”

“…Immunohistochemistry was used to investigate desmin aggregation, regeneration, and myosin isoforms that had altered gene expression as well as peptide expression in the proteomic profile. Staining was performed for desmin (1:100 anti-desmin-mouse monoclonal D33; Agilent Technologies, Santa Clara CA) and MHCd (1:50 mouse monoclonal anti-MHCd; Leica Biosystems, Buffalo Grove, IL) as previously described (63, 64). For MYH13 staining, flash-frozen muscle samples 7 μm thick were placed on charged slides and air-dried overnight at 25°C.…”

Candidate gene expression and coding sequence variants in Warmblood horses with myofibrillar myopathy

“…A diagnosis of myofibrillar myopathy (MFM) in Arabian and Warmblood horses (WB) is based on histological features that overlap with human MFM, including desmin aggregates and myofibrillar disarray in skeletal muscle fibres 1,2 . Clinical signs associated with MFM WB are usually apparent by 11 years of age and include exercise intolerance, a reluctance to move forward under saddle and a mild lameness not attributable to an underlying orthopaedic cause 1–3 . In humans, clinical signs of MFM are often apparent after the 4th decade of life 4–8 and include progressive muscle atrophy and the potential for respiratory compromise, cardiomyopathy and death 4,5,9,10 .…”

“…In humans, clinical signs of MFM are often apparent after the 4th decade of life 4–8 and include progressive muscle atrophy and the potential for respiratory compromise, cardiomyopathy and death 4,5,9,10 . Cardiac impairment, the severity and progression of muscle atrophy as well as the extent of ectopic protein aggregation appear to be more marked in human patients with MFM than MFM‐affected WB 1,11,12 …”

Clinical insights: Lameness diagnosis in sports horses

“…Myofibrillar myopathy has been described in endurance horses (mostly Arabian and Arabian crosses) with intermittent signs of muscle pain and stiffness after exercise 18 . The same authors reported myofibrillar myopathy in a group of Warmblood horses showing exercise intolerance, reluctance to go forward, stiffness and poorly localised lameness 19 . In most horses muscle biopsy was performed due to inconclusive diagnostic anaesthesia.…”