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PloS one2026; 21(1); e0341655; doi: 10.1371/journal.pone.0341655

Aberrant skeletal muscle morphogenesis and myofiber differentiation characterize equine myotonic dystrophy.

Abstract: Equine myotonic dystrophy (eMD) is a rare neuromuscular disorder of undetermined origin marked by muscle hypertrophy and stiffness, dystrophic muscle histopathology, and myotonic discharges. In humans, myotonic dystrophy (DM) arises from trinucleotide repeat expansions in dystrophia myotonica protein kinase (DMPK) (DM1) or tetranucleotide expansions in cellular nucleic acid-binding protein (CNBP) (DM2), which disrupt mRNA processing and induce embryonic splicing patterns across multiple genes. In 6 eMD Quarter Horse types, (2-36 months-of-age) and 8 control Quarter Horses we determined: (1) fiber type composition of triceps, gluteal, and semimembranosus muscles; (2) differential gene (DEG) and protein (DEP) expression using transcriptomic and proteomic analyses; (3) presence of repeat expansions in transcripts of DMPK or CNBP and (4) exon 7 retention in CLCN1 or exon 22 splicing in ATP2A1. Predominance and clustering of type 1 fibers, expression of embryonic myosin, and upregulated mitochondrial and sarcomeric DEPs characterized eMD hindlimb musculature. Gene ontology (GO) analysis of 730 upregulated DEGs identified numerous GO terms related to morphogenesis of mesoderm-derived tissues and upregulated genes impacting myoD expression in eMD muscle. Top upregulated DEG involved myogenesis (MYOZ2, SBK2, SBK3, PAMR1), neurons, transcription/translation, cytoskeleton, basement/plasma membranes, and calcium binding/transport. Top upregulated proteins also impacted muscle morphogenesis (MUSTN1, CSRP3, TMSBX4, PDLIM, CALD1) as well as categories of mitochondria, sarcomere, extracellular matrix/ basement membrane, transcription, translation, cell cycle regulation, neurons amongst others. Downregulated DEP primarily impacted mitochondria, the sarcomere and glycogen metabolism. Notably, unlike human myotonic dystrophy, trinucleotide repeat expansions were not found in the DMPK 3'UTR (CTG)n nor tetranucleotide repeat expansions (CCTG)n in intron 1 of CNBP. Isoforms of CLCN1 containing fetal exon 7 were detected in equal frequency in eMD and control muscle and exon 22 was not alternatively spliced in ATP2A1 as has been found in DM1. Thus, distinct from DM1 and DM2, eMD is driven by unique molecular mechanisms impacting skeletal muscle morphogenesis, neurons and regulation of gene transcription/translation that alter fiber type composition, distribution and morphology. The origin of myotonia does not appear to be driven by a mutation in CLCN1 or retention of exon CLCN 7. Expanded splice site analysis and further research is warranted to elucidate the cause of myotonia and the distinct etiology of eMD.
Copyright: © 2026 Valberg et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Publication Date: 2026-01-29 PubMed ID: 41610137PubMed Central: PMC12854428DOI: 10.1371/journal.pone.0341655Google Scholar: Lookup
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  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

Overview

  • This research investigates equine myotonic dystrophy (eMD), a rare muscle disorder in horses, by examining muscle fiber composition, gene and protein expression, and genetic features to understand how it differs from human myotonic dystrophy at molecular and cellular levels.

Background and Objectives

  • Equine myotonic dystrophy (eMD) is a neuromuscular disorder characterized by muscle hypertrophy (enlargement), stiffness, dystrophic muscle changes, and abnormal muscle electrical activity called myotonic discharges.
  • Human myotonic dystrophy (DM) arises from specific repeat expansions in genes DMPK (DM1) or CNBP (DM2), which cause mRNA processing defects and abnormal gene splicing resulting in disease symptoms.
  • The study focused on six young eMD-affected Quarter Horses and eight control Quarter Horses to explore differences in:
    • Muscle fiber types in various muscles (triceps, gluteal, semimembranosus)
    • Gene and protein expression patterns through transcriptomic and proteomic analyses
    • Presence of known repeat expansions in DMPK and CNBP genes typical of human DM
    • Specific alternative splicing events in muscle-related genes (exon 7 retention in CLCN1, exon 22 splicing in ATP2A1)

Key Findings: Muscle Fiber and Molecular Characteristics

  • Hindlimb muscles of eMD horses showed predominance and clustering of type 1 muscle fibers, which are slow-twitch fibers usually adapted for endurance.
  • Expression of embryonic myosin was observed, indicating abnormal muscle differentiation or regeneration processes.
  • Upregulation of numerous mitochondrial and sarcomeric proteins was detected, suggesting changes in energy metabolism and muscle contractile machinery.
  • Gene Ontology (GO) analysis of 730 upregulated genes revealed enrichment in processes related to the development (“morphogenesis”) of mesodermal tissues, which include skeletal muscle.
  • Some upregulated genes influence myoD expression, a critical regulator of muscle differentiation.

Specific Genes and Proteins Impacted

  • Top upregulated genes involved in:
    • Myogenesis: MYOZ2, SBK2, SBK3, PAMR1 (genes regulating muscle formation and growth)
    • Neuronal functions, transcription and translation mechanisms, cytoskeletal structure, cell membranes, and calcium regulation
  • Top upregulated proteins included MUSTN1, CSRP3, TMSBX4, PDLIM, and CALD1, which play roles in muscle morphogenesis, mitochondrial function, sarcomere structure, extracellular matrix and basement membrane organization, transcription, translation, cell cycle, and neuron-related functions.
  • Downregulated proteins mainly affected mitochondria, sarcomere components, and glycogen metabolism, indicating possible energy utilization issues and structural muscle defects.

Genetic and Splicing Analyses

  • Unlike human DM, no trinucleotide (CTG)n repeat expansions were found in the 3’ untranslated region (UTR) of the DMPK gene in eMD horses.
  • No tetranucleotide (CCTG)n repeat expansions were detected in intron 1 of CNBP, another gene linked to human myotonic dystrophy.
  • Alternative splicing analysis showed that the fetal isoform of the chloride channel gene CLCN1, containing exon 7, appeared equally in eMD and control horses, suggesting no abnormal splicing there.
  • Similarly, exon 22 of the calcium ATPase gene ATP2A1 was not alternatively spliced in eMD horses, a contrast to human DM1 where it is commonly affected.

Conclusions and Implications

  • eMD is molecularly distinct from human DM1 and DM2, indicating different underlying mechanisms beyond the known repeat expansions.
  • The disease involves abnormal skeletal muscle development, altered fiber composition and distribution, and changes in neuronal and gene regulatory pathways.
  • The cause of myotonia (muscle stiffness) in eMD does not appear to result from mutations or abnormal splicing of CLCN1 or ATP2A1 genes, which are implicated in human myotonia.
  • Further investigations, including expanded splice site analyses and molecular studies, are needed to identify the specific genetic or molecular triggers of eMD.

Significance

  • This study enhances understanding of equine myotonic dystrophy by differentiating it from human forms at the molecular level.
  • It highlights unique molecular signatures affecting muscle morphogenesis and neuronal functions in horses.
  • The findings encourage further research into novel molecular pathways that may contribute to muscle diseases in animals and possibly provide comparative insights for human muscle disorders.

Cite This Article

APA
Valberg SJ, Williams ZJ, Ames EG, Mickelson JR, Nout-Lomas YS, Landolt G, Sanz M, Gardner K. (2026). Aberrant skeletal muscle morphogenesis and myofiber differentiation characterize equine myotonic dystrophy. PLoS One, 21(1), e0341655. https://doi.org/10.1371/journal.pone.0341655

Publication

PloS one
ISSN: 1932-6203
NlmUniqueID: 101285081
Country: United States
Language: English
Volume: 21
Issue: 1
Pages: e0341655
PII: e0341655

Researcher Affiliations

Valberg, Stephanie J
  • Michigan State University, Large Animal Clinical Sciences, College of Veterinary Medicine, East Lansing, Michigan, United States of America.
Williams, Zoë J
  • Department of Pediatrics, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
Ames, Elizabeth G
  • Department of Pathobiology, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota, United States of America.
Mickelson, James R
  • Department of Veterinary Clinical Sciences, Washington State University, Pullman Washington, United States of America.
Nout-Lomas, Yvette S
  • Department of Pediatrics, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
Landolt, Gabriele
  • Department of Pediatrics, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
Sanz, Macarena
  • Department of Veterinary Clinical Sciences, Washington State University, Pullman Washington, United States of America.
Gardner, Keri
  • Michigan State University, Large Animal Clinical Sciences, College of Veterinary Medicine, East Lansing, Michigan, United States of America.

MeSH Terms

  • Animals
  • Myotonic Dystrophy / pathology
  • Myotonic Dystrophy / genetics
  • Myotonic Dystrophy / veterinary
  • Myotonic Dystrophy / metabolism
  • Horses
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / metabolism
  • Muscle Fibers, Skeletal / pathology
  • Muscle Fibers, Skeletal / metabolism
  • Cell Differentiation
  • Horse Diseases / genetics
  • Horse Diseases / pathology
  • Horse Diseases / metabolism
  • Myotonin-Protein Kinase / genetics
  • Morphogenesis / genetics
  • Trinucleotide Repeat Expansion

Conflict of Interest Statement

Dr. Valberg directs the Neuromuscular Diagnostic Laboratory and receives financial remuneration for interpreting muscle biopsies. She also received royalties for genetic tests PSSM1 and GBED and feed products for horses. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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