AUF1 Gene Transfer Increases Exercise Performance and Improves Skeletal Muscle Deficit in Adult Mice

Abstract MuRF1 (TRIM63) is a muscle-specific E3 ubiquitin ligase and component of the ubiquitin proteasome system. MuRF1 is transcriptionally upregulated under conditions that cause muscle loss, in both rodents and humans, and is a recognized marker of muscle atrophy. In this study, we used in vivo electroporation to determine if MuRF1 overexpression alone can cause muscle atrophy and, in combination with ubiquitin proteomics, identify the endogenous MuRF1 substrates in skeletal muscle. Overexpression of MuRF1 in adult mice increases ubiquitination of myofibrillar and sarcoplasmic proteins, increases expression of genes associated with neuromuscular junction instability, and causes muscle atrophy. A total of 169 ubiquitination sites on 56 proteins were found to be regulated by MuRF1. MuRF1-mediated ubiquitination targeted both thick and thin filament contractile proteins, as well as, glycolytic enzymes, deubiquitinases, p62, and VCP. These data reveal a potential role for MuRF1 in not only the breakdown of the sarcomere, but also the regulation of metabolism and other proteolytic pathways in skeletal muscle.

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Single-nucleus RNA-seq and FISH identify coordinated transcriptional activity in mammalian myofibers

Nature Communications ◽

10.1038/s41467-020-18789-8 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 2

Author(s):

Matthieu Dos Santos ◽

Stéphanie Backer ◽

Benjamin Saintpierre ◽

Brigitte Izac ◽

Muriel Andrieu ◽

...

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Transcription Factors ◽

Neuromuscular Junction ◽

Heavy Chain ◽

Transcriptional Activity ◽

Rna Seq ◽

Hybrid Fibers ◽

Adult Mice ◽

Single Nucleus

Abstract Skeletal muscle fibers are large syncytia but it is currently unknown whether gene expression is coordinately regulated in their numerous nuclei. Here we show by snRNA-seq and snATAC-seq that slow, fast, myotendinous and neuromuscular junction myonuclei each have different transcriptional programs, associated with distinct chromatin states and combinations of transcription factors. In adult mice, identified myofiber types predominantly express either a slow or one of the three fast isoforms of Myosin heavy chain (MYH) proteins, while a small number of hybrid fibers can express more than one MYH. By snRNA-seq and FISH, we show that the majority of myonuclei within a myofiber are synchronized, coordinately expressing only one fast Myh isoform with a preferential panel of muscle-specific genes. Importantly, this coordination of expression occurs early during post-natal development and depends on innervation. These findings highlight a previously undefined mechanism of coordination of gene expression in a syncytium.

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Expression of the Irisin Precursor FNDC5 in Skeletal Muscle Correlates With Aerobic Exercise Performance in Patients With Heart Failure

Circulation Heart Failure ◽

10.1161/circheartfailure.112.969543 ◽

2012 ◽

Vol 5 (6) ◽

pp. 812-818 ◽

Cited By ~ 119

Author(s):

Stewart H. Lecker ◽

Alexandra Zavin ◽

Peirang Cao ◽

Ross Arena ◽

Kelly Allsup ◽

...

Keyword(s):

Heart Failure ◽

Skeletal Muscle ◽

Aerobic Exercise ◽

Exercise Performance ◽

Patients With Heart Failure

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HIRA stabilizes skeletal muscle lineage identity

Nature Communications ◽

10.1038/s41467-021-23775-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Joana Esteves de Lima ◽

Reem Bou Akar ◽

Léo Machado ◽

Yuefeng Li ◽

Bernadette Drayton-Libotte ◽

...

Keyword(s):

Skeletal Muscle ◽

Cell Lineage ◽

Promoter Regions ◽

Cell Fates ◽

Regulatory Regions ◽

Muscle Stem Cells ◽

Adult Mice ◽

H3k4me3 Mark ◽

Muscle Genes ◽

Muscle Gene

AbstractThe epigenetic mechanisms coordinating the maintenance of adult cellular lineages and the inhibition of alternative cell fates remain poorly understood. Here we show that targeted ablation of the histone chaperone HIRA in myogenic cells leads to extensive transcriptional modifications, consistent with a role in maintaining skeletal muscle cellular identity. We demonstrate that conditional ablation of HIRA in muscle stem cells of adult mice compromises their capacity to regenerate and self-renew, leading to tissue repair failure. Chromatin analysis of Hira-deficient cells show a significant reduction of histone variant H3.3 deposition and H3K27ac modification at regulatory regions of muscle genes. Additionally, we find that genes from alternative lineages are ectopically expressed in Hira-mutant cells via MLL1/MLL2-mediated increase of H3K4me3 mark at silent promoter regions. Therefore, we conclude that HIRA sustains the chromatin landscape governing muscle cell lineage identity via incorporation of H3.3 at muscle gene regulatory regions, while preventing the expression of alternative lineage genes.

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