Dataset Information

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.

SUBMITTER: Lloyd EM

PROVIDER: S-EPMC6457631 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Lloyd Erin M EM Xu Hongyang H Murphy Robyn M RM Grounds Miranda D MD Pinniger Gavin J GJ

PloS one 20190410 4

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 month ...[more]

PMID: 30970035

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Project description:The different skeletal muscle fiber types exhibit distinctively different physiological and metabolic properties, and have been linked to both human metabolic diseases and meat quality traits in livestock. Circular RNAs (circRNAs) are a new class of endogenous RNA regulating gene expression, but regulatory mechanisms of skeletal muscle fibers involved in circRNAs remain poorly understood. Here, we constructed circRNA expression profiles of three fast-twitch biceps femoris (Bf) and three slow-twitch soleus (Sol) muscles in pigs using RNA-seq and identified 16,342 distinct circRNA candidates. Notably, 242 differentially expressed (DE) circRNAs between Bf and Sol muscles were identified, including 105 upregulated and 137 downregulated circRNAs, and are thus potential candidates for the regulation of skeletal muscle fiber conversion. Moreover, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of host genes of DE circRNAs revealed that host genes were mainly involved in skeletal muscle fiber-related GO terms (e.g., muscle contraction, contractile fiber part, and Z disk) and skeletal muscle fiber-related signaling pathways (e.g., AMPK and cGMP-PKG). We also constructed co-expression networks of DE circRNA-miRNA-mRNA using previously acquired high-throughput sequencing mRNA and miRNA data, from which 112 circRNA-miRNA and 95 miRNA-mRNA interactions were identified. Multiple circRNAs essentially serve as a sponge for miR-499-5p, which is preferentially expressed in slow-twitch muscle and reduces the severity of Duchenne muscular dystrophy (DMD). Taken together, a series of novel candidate circRNAs involved in the growth and development of porcine skeletal muscle was identified. Furthermore, they provide a comprehensive circRNA resource for further in-depth research on the regulatory mechanisms of circRNA in the formation of skeletal muscle fiber, and may provide insights into human skeletal muscle diseases.

Project description:BackgroundScallops possess striated and catch adductor muscles, which have different structure and contractile properties. The striated muscle contracts very quickly for swimming, whereas the smooth catch muscle can keep the shells closed for long periods with little expenditure of energy. In this study, we performed proteomic and transcriptomic analyses of differences between the striated (fast) and catch (slow) adductor muscles in Yesso scallop Patinopecten yessoensis.ResultsTranscriptomic analysis reveals 1316 upregulated and 8239 downregulated genes in slow compared to fast adductor muscle. For the same comparison, iTRAQ-based proteomics reveals 474 differentially expressed proteins (DEPs), 198 up- and 276 downregulated. These DEPs mainly comprise muscle-specific proteins of the sarcoplasmic reticulum, extracellular matrix, and metabolic pathways. A group of conventional muscle proteins-myosin heavy chain, myosin regulatory light chain, myosin essential light chain, and troponin-are enriched in fast muscle. In contrast, paramyosin, twitchin, and catchin are preferentially expressed in slow muscle. The association analysis of proteomic and transcriptomic data provides the evidences of regulatory events at the transcriptional and posttranscriptional levels in fast and slow muscles. Among 1236 differentially expressed unigenes, 22.7% show a similar regulation of mRNA levels and protein abundances. In contrast, more unigenes (53.2%) exhibit striking differences between gene expression and protein abundances in the two muscles, which indicates the existence of fiber-type specific, posttranscriptional regulatory events in most of myofibrillar proteins, such as myosin heavy chain, titin, troponin, and twitchin.ConclusionsThis first, global view of protein and mRNA expression levels in scallop fast and slow muscles reveal that regulatory mechanisms at the transcriptional and posttranscriptional levels are essential in the maintenance of muscle structure and function. The existence of fiber-type specific, posttranscriptional regulatory mechanisms in myofibrillar proteins will greatly improve our understanding of the molecular basis of muscle contraction and its regulation in non-model invertebrates.

Dataset Information

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

Publications

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

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