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MRF4 negatively regulates adult skeletal muscle growth by repressing MEF2 activity

ABSTRACT: The myogenic regulatory factor MRF4 is expressed at high levels in myofibers of adult skeletal muscle, but its function is unknown. Here we show that knockdown of MRF4 in adult muscle causes hypertrophy and prevents denervation-induced atrophy. This effect is accompanied by increased protein synthesis and the widespread activation of genes involved in muscle contraction, excitation-contraction coupling and energy metabolism, many of which are known targets of MEF2 transcription factors. Genes regulated by MEF2 represent the top-ranking gene set enriched after Mrf4 RNAi, and a MEF2 reporter is inhibited by co-transfected MRF4 and activated by Mrf4 RNAi. The role of MEF2 in mediating the effect of MRF4 knockdown is supported by the finding that Mrf4 RNAi-dependent increase in fiber size is prevented by dominant negative MEF2, while constitutively active MEF2 is able to induce myofiber hypertrophy. The nuclear localization of the MEF2 co-repressor HDAC4 is impaired by Mrf4 knockdown, suggesting that MRF4 acts by stabilizing a repressor complex that controls MEF2 activity. The demonstration that fiber size in adult skeletal muscle is controlled by the MRF4-MEF2 axis opens new perspectives in the search for therapeutic targets to prevent muscle wasting, in particular sarcopenia and cachexia. Adult innervated and denervated rat soleus muscles were transfected with shRNA to Mrf4 (M1) or to LacZ as a control. Muscles were dissected and examined after 7 days. For each group/condition we selected three different muscles (biological replicas).

ORGANISM(S): Rattus norvegicus

SUBMITTER: Silvio Bicciato

PROVIDER: E-GEOD-67069 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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MRF4 negatively regulates adult skeletal muscle growth by repressing MEF2 activity

Project description:The myogenic regulatory factor MRF4 is expressed at high levels in myofibers of adult skeletal muscle, but its function is unknown. Here we show that knockdown of MRF4 in adult muscle causes hypertrophy and prevents denervation-induced atrophy. This effect is accompanied by increased protein synthesis and the widespread activation of genes involved in muscle contraction, excitation-contraction coupling and energy metabolism, many of which are known targets of MEF2 transcription factors. Genes regulated by MEF2 represent the top-ranking gene set enriched after Mrf4 RNAi, and a MEF2 reporter is inhibited by co-transfected MRF4 and activated by Mrf4 RNAi. The role of MEF2 in mediating the effect of MRF4 knockdown is supported by the finding that Mrf4 RNAi-dependent increase in fiber size is prevented by dominant negative MEF2, while constitutively active MEF2 is able to induce myofiber hypertrophy. The nuclear localization of the MEF2 co-repressor HDAC4 is impaired by Mrf4 knockdown, suggesting that MRF4 acts by stabilizing a repressor complex that controls MEF2 activity. The demonstration that fiber size in adult skeletal muscle is controlled by the MRF4-MEF2 axis opens new perspectives in the search for therapeutic targets to prevent muscle wasting, in particular sarcopenia and cachexia.

2016-07-15 | GSE67069 | GEO

Expression data from longissimus dorsi muscle of Meishan pigs

Project description:The skeletal muscle growth and development is a very complicated but precisely regulated process with interwoven molecular mechanisms. Skeletal muscle is a very heterogeneous tissue that is made up of a large variety of functionally diverse fiber types. Muscle mass is therefore largely determined by the number and size of those fibres. These fibre characteristics are determined by hyperplasia before birth and by hypertrophy after. Around 65 dpc and three postnatal stages (newborn, 3 days; young, 60 days; and mature, 120 days) are key time points in swine skeletal muscle growth and development. We used microarrays to detail the global programme of gene expression underlying porcine skeletal muscle growth and development. Porcine longissimus dorsi muscles were selected at four stages of development for RNA extraction and hybridization on Affymetrix microarrays. We sought to investigate the global gene expression patterns accompanying the skeletal muscle development. To that end, we selected longissimus dorsi muscles at four time-points: 65 days post coitus, 3 days, 60 days and 120 days afterbirth.

2011-07-01 | E-GEOD-24689 | biostudies-arrayexpress

Down-regulation of JunB by RNAi in mouse muscles in vivo

Project description:The size of skeletal muscles, like that of all cells, is precisely regulated by intracellular signaling networks that determine the balance between overall rates of protein synthesis and degradation. Muscle fiber growth and protein synthesis are stimulated by the IGF1/Akt/mTOR pathway, and muscle wasting, as occurs with disuse, denervation, fasting, and various systemic diseases (e.g. cancer, sepsis) results from excessive protein breakdown in muscle and induction of a set of atrophy-related genes by the FoxO transcription factors. Here we show that the transcription factor JunB is also a major regulator of growth and atrophy of adult (post mitotic) muscle cells. We found that in atrophying myotubes, JunB protein was excluded from the nucleus and that decreasing JunB expression by RNAi in muscles of adults reduced fiber size. Furthermore, in normal muscles of adult mice JunB over-expression increased fiber diameter dramatically (up to 40% in 7 days), and stimulated protein synthesis, but unlike IGF-1 or insulin, JunB did not activate the Akt/mTOR pathway. Importantly, when JunB was transfected into denervated muscles to maintain its level high, fiber atrophy was prevented, and the induction of the critical atrophy-associated ubiquitin-ligases, atrogin-1 and MuRF-1, was greatly reduced. JunB inhibited their induction by impairing FoxO3 binding to their promoters and thus reduced the stimulation of protein breakdown by FoxO3. Thus JunB is important, not only in dividing populations, but also in mature skeletal muscle where it is required for the maintenance of muscle size and can induce rapid hypertrophy and block atrophy.

2010-01-01 | GSE18664 | GEO

Transcriptional profiling of adult wild-type IFM and leg muslce in comparison to salm RNAi IFM.

Project description:Transcriptional profiling comparing adult wild-type indirect flight muscle (IFM) with wild-type leg muscle and salm RNAi IFM (Mef2-GAL4, UASsalmIR). We used 2 different salm hairpin constructs for the experiments, TF3029 and TF101052, both available from the VDRC Drosophila stock centre. Experiments were done in biological duplicates + 1 technical replicate (1 labeled sample was hybridized on a different array)

2011-03-01 | E-GEOD-27502 | biostudies-arrayexpress

The miRNA Transcriptome directly Reflect the Physiological and Biochemical Differences between Red, White and Intermediate Muscle Fiber Types

Project description:MicroRNAs (miRNAs) are small non-coding RNAs that can regulate the expression of their target genes at post-transcriptional level. Skeletal muscle comprises different ï¬?ber types that can be broadly classified as red, intermediate and white fiber types. Recently, a set of miRNAs were identified to be expressed on a fiber type-specific manner between red and white fiber types. Nonetheless, an integral explanation of the miRNA transcriptome differences in all three fiber types is long overdue. Herein, we collected 15 kinds of porcine skeletal muscles from different anatomic locations, which were then clearly divided into red, white and intermediate fiber type based on the hierarchical clustering analysis for the ratios of myosin heavy chain (MHC) isoforms. We further illustrated that three muscles, which typically represented each muscle fiber type (i.e. red: peroneal longus (PL), intermediate: psoas major muscle (PMM), white: longissimus dorsi muscle (LDM)), have distinct metabolic patterns of mitochondrial and glycolytic enzyme levels. In addition, we constructed the small RNA libraries for PL, PMM and LDM using deep sequencing approach. Results showed that, the differentially expressed miRNAs were mainly enriched in PL and played a vital role in myogenesis and energy metabolism. Overall, this comprehensive analysis will contribute to a better understanding of the miRNA regulatory mechanism for the phenotypic diversity of skeletal muscles. 3 sample

2015-12-23 | E-GEOD-64523 | biostudies-arrayexpress

Transcription profiling of lamb Callipyge muscle types (ST, LD, SS, SM) at birth (T=0) and 12 weeks (T=12)

Project description:Microarrays were used for transcription profiling of skeletal muscle samples taken at birth, when the phenotype was not expressed, and 12 weeks of age from Callipyge and wild type sheep. The genes that underlie the expression of the phenotype rather than result from the fibre type change in the affected muscle have been identified. We used microarrays to detail the global programme of gene expression underlying the hypertrophy phenotype and identified distinct classes of regulated genes during this process. A working model that links the muscle hypertrophy phenotype with a core group of transcriptional coregulators is proposed. Experiment Overall Design: Gene expression analyses were performed primarily on longissimus dorsi skeletal muscle (LD) from Wild type (NN) and Callipyge (NCpat) sheep using Bovine Affymetrix GeneChip microarrays. Two developmental time-points were investigated in this study: newborn (within 5 days of birth; T0) and 11-12 weeks post-birth (T12). The muscle hypertrophy phenotype developed over the first 2-3 months and was associated with a significant change in muscle fibre type (Carpenter et al., 1996; Cockett et al., 1994; 1996; Kerth et al., 2003). One of the objectives of the gene expression analysis was to delineate between those genes that underlie the muscle hypertrophy in Callipyge sheep and those that result from the fibre type change in the affected muscle. To address this issue a comparison was undertaken of gene expression in wild type skeletal muscles with differing fibre type compositions to identify fibre type specific genes. These samples were taken from NN animals at T12. The three skeletal muscles used in this analysis were semimembranosis (SM), semitendinosis (ST) and longissimus dorsi (LD).

2008-11-07 | E-GEOD-5955 | biostudies-arrayexpress

Effect of p21 overexpression on skeletal muscle mRNA expression.

Project description:For additional details see Bongers et al, Spermine Oxidase Maintains Basal Skeletal Muscle Gene Expression and Fiber Size, and Is Strongly Repressed by Conditions that Cause Skeletal Muscle Atrophy . Am J Physiol Endocrinol Metab. 2014 [under review] Bilateral tibialis anterior muscles of C57BL/6 mice were harvested seven days after transfection with p21 or control plasmid.

2014-12-04 | E-GEOD-63007 | biostudies-arrayexpress

Effect of spermine oxidase overexpression on skeletal muscle mRNA expression.

2014-12-04 | E-GEOD-63006 | biostudies-arrayexpress

Expression data from mouse neonatal hindlimb muscles

Project description:During neonatal development, skeletal muscle grows dramatically by myonuclei accretion to existing fibers and hypertophic growth of fibers with protein synthesis. To understand molecular mechanism underlying neonatal muscle growth, we used microarray to profile the global program of gene expressions especially involved in myoblast fusion, migration, and muscle fiber growth by itself. Mouse hindlimb muscles at postnatal day (P) 2, 7, and 14 were isolated and used for RNA extraction and hybridyzation on microarrays. We used three biological replicates for each time point.

2015-12-08 | E-GEOD-75774 | biostudies-arrayexpress

The RNA binding protein Arrest (Aret) regulates myofibril maturation in Drosophila flight muscle

Project description:In Drosophila, fibrillar flight muscles (IFMs) enable flight, while tubular muscles mediate other body movements. Here, we use RNA-sequencing and isoform-specific reporters to show that spalt major (salm) determines fibrillar muscle physiology by regulating transcription and alternative splicing of a large set of sarcomeric proteins. We identify the RNA binding protein Arrest (Aret, Bruno) as downstream of salm. Aret shuttles between cytoplasm and nuclei, and is essential for myofibril maturation and sarcomere growth of IFMs. Molecularly, Aret regulates IFM-specific transcription and splicing of various sarcomeric targets, including Stretchin and wupA (TnI), and thus maintains muscle fiber integrity. As Aret and its sarcomeric targets are evolutionarily conserved, similar principles may regulate mammalian muscle morphogenesis. 9 samples from Drosophila melanogaster were analyzed in duplicate: control dissected wildtype flight muscle at 30h APF, 72h APF and 0 day adult, jump muscle and whole leg from 1d adult and RNAi/mutant conditions for salm (1d flight muscle) and aret (30h, 72h and 1d flight muscle)

2014-12-23 | E-GEOD-63707 | biostudies-arrayexpress

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