Aberrant skeletal muscle morphogenesis and myofiber differentiation characterize equine myotonic dystrophy.
Authors: Valberg Stephanie J, Williams Zoë J, Ames Elizabeth G, Mickelson James R, Nout-Lomas Yvette S, Landolt Gabriele, Sanz Macarena, Gardner Keri
Journal: PloS one
Summary
Equine myotonic dystrophy is a rare but clinically significant neuromuscular condition characterised by muscle hypertrophy, stiffness, and myotonic discharges; whilst human myotonic dystrophy arises from well-characterised trinucleotide or tetranucleotide repeat expansions, the molecular basis of the equine form has remained unknown. Valberg and colleagues performed comprehensive transcriptomic and proteomic profiling of affected hindlimb muscles from six affected Quarter Horse foals (aged 2–36 months) and eight controls, alongside targeted genetic screening for the mutations responsible in human disease. Rather than the repeat expansions seen in human myotonic dystrophy, equine disease is characterised by altered skeletal muscle morphogenesis—with predominance of type 1 fibres, embryonic myosin expression, and widespread upregulation of genes and proteins controlling muscle development (including MYOZ2, MUSTN1, and CSRP3), alongside dysregulation of mitochondrial, sarcomeric, and calcium-handling pathways. The chloride channel splicing abnormality (CLCN1 exon 7 retention) and calcium-release channel variant (ATP2A1 exon 22 splicing) implicated in human disease were conspicuously absent in equine cases, indicating a fundamentally distinct molecular aetiology. These findings suggest that equine myotonic dystrophy warrants investigation of alternative genetic mechanisms and splice variants, with important implications for genetic testing, breeding decisions in affected families, and understanding whether therapeutic approaches validated in human myotonic dystrophy would be applicable to the equine condition.
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Practical Takeaways
- •eMD is a distinct neuromuscular condition with unique molecular mechanisms; genetic testing for human DM mutations will not identify affected horses
- •The fundamental muscle pathology involves aberrant fiber development and morphogenesis rather than the ion channel defects seen in human myotonic dystrophy
- •Further research into alternative splice site mechanisms and transcriptional regulation is needed to understand disease pathogenesis and develop targeted interventions
Key Findings
- •eMD is characterized by predominance of type 1 fibers with embryonic myosin expression and upregulated mitochondrial/sarcomeric proteins, distinct from human myotonic dystrophy mechanisms
- •730 upregulated differentially expressed genes in eMD muscle relate to mesoderm morphogenesis, myogenesis, and myoD expression regulation
- •Unlike human DM1 and DM2, eMD does not involve trinucleotide or tetranucleotide repeat expansions in DMPK or CNBP genes
- •CLCN1 exon 7 retention and ATP2A1 exon 22 splicing patterns do not differ between eMD and control horses, suggesting alternative etiology for myotonia