Loss‐ And Gain of Function Mutations in the Type 1 IP3 Receptor (IP3R1) Modify Agonist‐Evoked Vasoactive Responses in Cerebral and Skeletal Muscle Resistance Arteries From 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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The effects of exercise training versus intensive insulin treatment on skeletal muscle fibre content in type 1 diabetes mellitus rodents

Lipids in Health and Disease ◽

10.1186/s12944-021-01494-w ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

David P. McBey ◽

Michelle Dotzert ◽

C. W. J. Melling

Keyword(s):

Diabetes Mellitus ◽

Skeletal Muscle ◽

Type 1 Diabetes ◽

Exercise Training ◽

Muscle Fibre ◽

Lipid Content ◽

Fibre Type ◽

Insulin Treatment ◽

Type I

Abstract Background Intensive-insulin treatment (IIT) strategy for patients with type 1 diabetes mellitus (T1DM) has been associated with sedentary behaviour and the development of insulin resistance. Exercising patients with T1DM often utilize a conventional insulin treatment (CIT) strategy leading to increased insulin sensitivity through improved intramyocellular lipid (IMCL) content. It is unclear how these exercise-related metabolic adaptations in response to exercise training relate to individual fibre-type transitions, and whether these alterations are evident between different insulin strategies (CIT vs. IIT). Purpose: This study examined glycogen and fat content in skeletal muscle fibres of diabetic rats following exercise-training. Methods Male Sprague-Dawley rats were divided into four groups: Control-Sedentary, CIT- and IIT-treated diabetic sedentary, and CIT-exercised trained (aerobic/resistance; DARE). After 12 weeks, muscle-fibre lipids and glycogen were compared through immunohistochemical analysis. Results The primary findings were that both IIT and DARE led to significant increases in type I fibres when compared to CIT, while DARE led to significantly increased lipid content in type I fibres compared to IIT. Conclusions These findings indicate that alterations in lipid content with insulin treatment and DARE are primarily evident in type I fibres, suggesting that muscle lipotoxicity in type 1 diabetes is muscle fibre-type dependant.

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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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Electromechanical delay components during skeletal muscle contraction and relaxation in patients with myotonic dystrophy type 1

Neuromuscular Disorders ◽

10.1016/j.nmd.2015.09.013 ◽

2016 ◽

Vol 26 (1) ◽

pp. 60-72 ◽

Cited By ~ 18

Author(s):

Fabio Esposito ◽

Emiliano Cè ◽

Susanna Rampichini ◽

Eloisa Limonta ◽

Massimo Venturelli ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Contraction ◽

Myotonic Dystrophy ◽

Myotonic Dystrophy Type 1 ◽

Myotonic Dystrophy Type ◽

Electromechanical Delay ◽

Skeletal Muscle Contraction ◽

Contraction And Relaxation

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Human growth hormone treatment of hypophysectomized rats increases the proportion of type-1 fibres in skeletal muscle

Journal of Endocrinology ◽

10.1677/joe.0.1230429 ◽

1989 ◽

Vol 123 (3) ◽

pp. 429-NP ◽

Cited By ~ 48

Author(s):

C. M. Ayling ◽

B. H. Moreland ◽

J. M. Zanelli ◽

D. Schulster

Keyword(s):

Skeletal Muscle ◽

Fibre Type ◽

Extensor Digitorum Longus ◽

Human Growth ◽

Hormone Treatment ◽

Pituitary Hormones ◽

Extensor Digitorum ◽

Replacement Treatment ◽

Hypophysectomized Rats

ABSTRACT The studies describe alterations after hypophysectomy in the proportion of the type-1 and type-2 fibres in rat skeletal muscles, and the effects of replacement treatment with pituitary human (h) GH. Cytochemical analysis of myosin ATPase, succinate dehydrogenase and lactate dehydrogenase activities in sections of rat hind limb muscles were used as markers of fibre type and revealed that hypophysectomy reduced the proportion of type-1 fibres by 50% in soleus and in extensor digitorum longus muscles. This reduction in the proportion of type-1 fibres was accompanied by the appearance of transitional fibres (type 2C/1B). Following seven daily injections of hGH (60 mIU/day) to hypophysectomized rats, the proportion of type-1 fibres in both soleus and in extensor digitorum longus was increased with a concomitant reduction in the number of transitional fibres. After 11 days of treatment, all these transitional fibres had reverted back to type-1 fibres. Only hGH was observed to elicit this effect; injections of other pituitary hormones had no effect on the proportions of these transitional fibres. These alterations in fibre type occurred more rapidly than the changes reported after prolonged electrical stimulation of muscle or following extended exercise. These findings suggest that hypophysectomy and GH injection can result in a rapid alteration in the fibre composition of skeletal muscle, which may have important implications in terms of the resistance to fatigue and speed of contraction of the muscle. Journal of Endocrinology (1989) 123, 429–435

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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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