Dysferlin-deficiency has greater impact on function of slow muscles, compared with fast, in aged BLAJ mice

Erin M. Lloyd, Hongyang Xu, Robyn M. Murphy, Miranda D. Grounds, Gavin J. Pinniger

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Dysferlinopathies are a form of muscular dystrophy caused by gene mutations resulting in deficiency of the protein dysferlin. Symptoms manifest later in life in a muscle specific manner, although the pathomechanism is not well understood. This study compared the impact of dysferlin-deficiency on in vivo and ex vivo muscle function, and myofibre type composition in slow (soleus) and fast type (extensor digitorum longus; EDL) muscles using male dysferlin-deficient (dysf -/- ) BLAJ mice aged 10 months, compared with wild type (WT) C57Bl/6J mice. There was a striking increase in muscle mass of BLAJ soleus (+25%) (p<0.001), with no strain differences in EDL mass, compared with WT. In vivo measures of forelimb grip strength and wheel running capacity showed no strain differences. Ex vivo measures showed the BLAJ soleus had faster twitch contraction (-21%) and relaxation (-20%) times, and delayed post fatigue recovery (ps<0.05); whereas the BLAJ EDL had a slower relaxation time (+11%) and higher maximum rate of force production (+25%) (ps<0.05). Similar proportions of MHC isoforms were evident in the soleus muscles of both strains (ps>0.05); however, for the BLAJ EDL, there was an increased proportion of type IIx MHC isoform (+5.5%) and decreased type IIb isoform (-5.5%) (ps<0.01). This identification of novel differences in the impact of dysferlin-deficiency on slow and fast twitch muscles emphasises the importance of evaluating myofibre type specific effects to provide crucial insight into the mechanisms responsible for loss of function in dysferlinopathies; this is critical for the development of targeted future clinical therapies.

Original languageEnglish
Article numbere0214908
JournalPLoS One
Volume14
Issue number4
DOIs
Publication statusPublished - 1 Apr 2019

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Muscle
Muscles
muscles
mice
Protein Isoforms
Protein Deficiency
protein deficiencies
muscular dystrophy
Muscular Dystrophies
signs and symptoms (animals and humans)
Genes
mutation
therapeutics
Mutation
Chemical analysis
Proteins
genes
Dysferlinopathy
Therapeutics

Cite this

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title = "Dysferlin-deficiency has greater impact on function of slow muscles, compared with fast, in aged BLAJ mice",
abstract = "Dysferlinopathies are a form of muscular dystrophy caused by gene mutations resulting in deficiency of the protein dysferlin. Symptoms manifest later in life in a muscle specific manner, although the pathomechanism is not well understood. This study compared the impact of dysferlin-deficiency on in vivo and ex vivo muscle function, and myofibre type composition in slow (soleus) and fast type (extensor digitorum longus; EDL) muscles using male dysferlin-deficient (dysf -/- ) BLAJ mice aged 10 months, compared with wild type (WT) C57Bl/6J mice. There was a striking increase in muscle mass of BLAJ soleus (+25{\%}) (p<0.001), with no strain differences in EDL mass, compared with WT. In vivo measures of forelimb grip strength and wheel running capacity showed no strain differences. Ex vivo measures showed the BLAJ soleus had faster twitch contraction (-21{\%}) and relaxation (-20{\%}) times, and delayed post fatigue recovery (ps<0.05); whereas the BLAJ EDL had a slower relaxation time (+11{\%}) and higher maximum rate of force production (+25{\%}) (ps<0.05). Similar proportions of MHC isoforms were evident in the soleus muscles of both strains (ps>0.05); however, for the BLAJ EDL, there was an increased proportion of type IIx MHC isoform (+5.5{\%}) and decreased type IIb isoform (-5.5{\%}) (ps<0.01). This identification of novel differences in the impact of dysferlin-deficiency on slow and fast twitch muscles emphasises the importance of evaluating myofibre type specific effects to provide crucial insight into the mechanisms responsible for loss of function in dysferlinopathies; this is critical for the development of targeted future clinical therapies.",
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Dysferlin-deficiency has greater impact on function of slow muscles, compared with fast, in aged BLAJ mice. / Lloyd, Erin M.; Xu, Hongyang; Murphy, Robyn M.; Grounds, Miranda D.; Pinniger, Gavin J.

In: PLoS One, Vol. 14, No. 4, e0214908, 01.04.2019.

Research output: Contribution to journalArticle

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