Altered Tnnt3 characterizes selective weakness of fast fibers in mice overexpressing FSHD region gene 1 (FRG1)

Valentina Sancisi, Elena Germinario, Alessandra Esposito, Elisabetta Morini, Samantha Peron, Maurizio Moggio, Giuliano Tomelleri, Daniela Danieli-Betto, Rossella Tupler

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Facioscapulohumeral muscular dystrophy (FSHD), a common hereditary myopathy, is characterized by atrophy and weakness of selective muscle groups. FSHD is considered an autosomal dominant disease with incomplete penetrance and unpredictable variability of clinical expression within families. Mice overexpressing FRG1 (FSHD region gene 1), a candidate gene for this disease, develop a progressive myopathy with features of the human disorder. Here, we show that in FRG1-overexpressing mice, fast muscles, which are the most affected by the dystrophic process, display anomalous fast skeletal troponin T (fTnT) isoform, resulting from the aberrant splicing of the Tnnt3 mRNA that precedes the appearance of dystrophic signs. We determine that muscles of FRG1 mice develop less strength due to impaired contractile properties of fast-twitch fibers associated with an anomalous MyHC-actin ratio and a reduced sensitivity to Ca2+. We demonstrate that the decrease of Ca2+ sensitivity of fast-twitch fibers depends on the anomalous troponin complex and can be rescued by the substitution with the wild-type proteins. Finally, we find that the presence of aberrant splicing isoforms of TNNT3 characterizes dystrophic muscles in FSHD patients. Collectively, our results suggest that anomalous TNNT3 profile correlates with the muscle impairment in both humans and mice. On the basis of these results, we propose that aberrant fTnT represents a biological marker of muscle phenotype severity and disease progression.

Original languageEnglish
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume306
Issue number2
DOIs
Publication statusPublished - Jan 15 2014

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Facioscapulohumeral Muscular Dystrophy
Muscles
Genes
Muscular Diseases
Protein Isoforms
Troponin
Penetrance
Muscle Weakness
Atrophy
Disease Progression
Actins
Biomarkers
Phenotype
Messenger RNA
Proteins

Keywords

  • Aberrant splicing
  • FRG1
  • Muscle weakness
  • Muscular dystrophy
  • Troponin T

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Altered Tnnt3 characterizes selective weakness of fast fibers in mice overexpressing FSHD region gene 1 (FRG1). / Sancisi, Valentina; Germinario, Elena; Esposito, Alessandra; Morini, Elisabetta; Peron, Samantha; Moggio, Maurizio; Tomelleri, Giuliano; Danieli-Betto, Daniela; Tupler, Rossella.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 306, No. 2, 15.01.2014.

Research output: Contribution to journalArticle

Sancisi, Valentina ; Germinario, Elena ; Esposito, Alessandra ; Morini, Elisabetta ; Peron, Samantha ; Moggio, Maurizio ; Tomelleri, Giuliano ; Danieli-Betto, Daniela ; Tupler, Rossella. / Altered Tnnt3 characterizes selective weakness of fast fibers in mice overexpressing FSHD region gene 1 (FRG1). In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 2014 ; Vol. 306, No. 2.
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