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Epigenetic and Transcriptional Control of Skeletal Muscle Homeostasis, Regeneration, and Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 August 2023) | Viewed by 9492

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Special Issue Editors

Dr. Susanna Molinari

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Guest Editor

Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, 41125 Modena, Italy
Interests: transcription factors; alternative splicing; gene transcription; muscle stem cells; cell proliferation and differentiation; molecular basis of muscle homeostasis and plasticity

Dr. Carol Imbriano

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Guest Editor

Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 213/D, 41125 Modena, Italy
Interests: transcription factors; alternative splicing; gene transcription; muscle stem cells; cell proliferation and differentiation; molecular basis of cancer

Special Issue Information

Dear Colleagues,

The homeostasis of skeletal muscle and metabolic adaptations are key for whole-body metabolism in healthy individuals. Moreover, they both act as potential disease modifiers in human diseases, such as cardiovascular pathologies and cancer. Both transcriptional and epigenetic mechanisms regulate muscle mass maintenance and metabolism in response to intrinsic or extrinsic signals that induce cell-type-specific reprogramming. Moreover, there is bidirectional crosstalk between cell metabolism and both transcription factors and chromatin dynamics. Although the roles of many transcription factors have been well characterized during myogenesis, less is known about their activities in mature muscle homeostasis in health and disease. Therefore, studies aimed at dissecting novel molecular mechanisms that participate in muscle adaptations are of primary relevance for the development of novel treatments and diagnostic tools.

The main purpose of this Special Issue is to provide new experimental evidence on the role of transcriptional and epigenetic mechanisms at the basis of muscle homeostasis, and to understand their connection with the molecular pathways associated with muscle regeneration and disease. Original research and review articles will provide an overview of recent developments and an update of the current state of knowledge.

Dr. Susanna Molinari
Dr. Carol Imbriano
Guest Editors

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Keywords

skeletal muscle
homeostasis
muscle atrophy
muscle regeneration
degenerative muscle diseases
transcriptional regulation
epigenetic control of gene transcription
muscle metabolism
chromatin conformation

Published Papers (5 papers)

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Research

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19 pages, 3025 KiB

Open AccessArticle

Metformin Attenuates Slow-to-Fast Fiber Shift and Proteolysis Markers Increase in Rat Soleus after 7 Days of Rat Hindlimb Unloading

by Kristina A. Sharlo, Irina D. Lvova, Svetlana P. Belova, Ksenia A. Zaripova, Boris S. Shenkman and Tatiana L. Nemirovskaya

Int. J. Mol. Sci. 2023, 24(1), 503; https://doi.org/10.3390/ijms24010503 - 28 Dec 2022

Cited by 6 | Viewed by 1954

Abstract

Muscle unloading leads to signaling alterations that cause muscle atrophy and weakness. The cellular energy sensor AMPK can regulate myofiber-type shift, calcium-dependent signaling and ubiquitin-proteasome system markers. We hypothesized that the prevention of p-AMPK downregulation during the first week of muscle unloading would impede atrophy development and the slow-to-fast shift of soleus muscle fibers, and the aim of the study was to test this hypothesis. Thirty-two male Wistar rats were randomly assigned to four groups: placebo control (C), control rats treated with metformin (C + M), 7 days of hindlimb suspension (HS) + placebo (7HS), and 7 days of HS + metformin administration (7HS + M). In the soleus of the 7HS rats, we detected a slow-to-fast fiber-type shift as well as a significant downregulation of MEF-2D and p300 in the nuclei. In the 7HS group, we also found decreases in p-ACC (AMPK target) protein level and in the expression of E3 ubiquitin ligases and p-CaMK II protein level vs. the C group. The 7-day metformin treatment for soleus muscle unloading (1) prevented slow-to-fast fiber-type shift; (2) counteracted changes in the p-ACC protein level; (3) hindered changes in the nuclear protein level of the slow myosin expression activators MEF-2D and p300, but did not affect NFATc1 signaling; and (4) attenuated the unloading-induced upregulation of MuRF-1, atrogin-1, ubiquitin and myostatin mRNA expression, but did not prevent soleus muscle atrophy. Thus, metformin treatment during muscle disuse could be useful to prevent the decrease in the percentage of slow-type fatigue-resistant muscle fibers. Full article

(This article belongs to the Special Issue Epigenetic and Transcriptional Control of Skeletal Muscle Homeostasis, Regeneration, and Diseases)

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18 pages, 1657 KiB

Open AccessArticle

Transcriptome and Methylome Profiling in Rat Skeletal Muscle: Impact of Post-Weaning Protein Restriction

by Sihui Ma, Emi Hasegawa, Yuji Nakai, Huijuan Jia and Hisanori Kato

Int. J. Mol. Sci. 2022, 23(24), 15771; https://doi.org/10.3390/ijms232415771 - 12 Dec 2022

Viewed by 1499

Abstract

Skeletal muscle is programmable, and early-life nutritional stimuli may form epigenetic memory in the skeletal muscle, thus impacting adult muscle function, aging, and longevity. In the present study, we designed a one-month protein restriction model using post-weaning rats, followed by a two-month rebound feeding, to investigate how early-life protein restriction affects overall body growth and muscle development and whether these influences could be corrected by rebound feeding. We observed comprehensive alterations immediately after protein restriction, including retarded growth, altered biochemical indices, and disturbed hormone secretion. Transcriptome profiling of the gastrocnemius muscle followed by gene ontology analyses revealed that “myogenic differentiation functions” were upregulated, while “protein catabolism” was downregulated as a compensatory mechanism, with enhanced endoplasmic reticulum stress and undesired apoptosis. Furthermore, methylome profiling of the gastrocnemius muscle showed that protein restriction altered the methylation of apoptotic and hormone secretion-related genes. Although most of the alterations were reversed after rebound feeding, 17 genes, most of which play roles during muscle development, remained altered at the transcriptional level. In summary, early-life protein restriction may undermine muscle function in the long term and affect skeletal muscle development at the both transcriptional and methylation levels, which may hazard future muscle health. Full article

(This article belongs to the Special Issue Epigenetic and Transcriptional Control of Skeletal Muscle Homeostasis, Regeneration, and Diseases)

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16 pages, 2749 KiB

Open AccessArticle

Identification of Agents That Ameliorate Hyperphosphatemia-Suppressed Myogenin Expression Involved in the Nrf2/p62 Pathway in C2C12 Skeletal Muscle Cells

by Shu-Man Hsieh Li, Shu-Ting Liu, Yung-Lung Chang, Gunng-Shinng Chen and Shih-Ming Huang

Int. J. Mol. Sci. 2022, 23(23), 15324; https://doi.org/10.3390/ijms232315324 - 5 Dec 2022

Viewed by 1869

Abstract

Hyperphosphatemia can occur as a result of reduced phosphate (P_i) excretion in cases of kidney dysfunction, which can induce muscle wasting and suppress myogenic differentiation. Higher P_i suppresses myogenic differentiation and promotes muscle atrophy through canonical (oxidative stress-mediated) and noncanonical (p62-mediated) activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. However, the crosstalk between myogenin and Nrf2/p62 and potential drug(s) for the regulation of myogenin expression needed to be addressed. In this study, we further identified that myogenin may negatively regulate Nrf2 and p62 protein levels in the mouse C2C12 muscle cell line. In the drug screening analysis, we identified N-acetylcysteine, metformin, phenformin, berberine, 4-chloro-3-ethylphenol, cilostazol, and cilomilast as ameliorating the induction of Nrf2 and p62 expression and reduction in myogenin expression that occur due to high P_i. We further elucidated that doxorubicin and hydrogen peroxide reduced the amount of myogenin protein mediated through the Kelch-like ECH-associated protein 1/Nrf2 pathway, differently from the mechanism of high Pi. The dual functional roles of L-ascorbic acid (L-AA) were found to be dependent on the working concentration, where concentrations below 1 mM L-AA reversed the effect of high P_i on myogenin and those above 1 mM L-AA had a similar effect of high P_i on myogenin when used alone. L-AA exacerbated the effect of hydrogen peroxide on myogenin protein and had no further effect of doxorubicin on myogenin protein. In summary, our results further our understanding of the crosstalk between myogenin and Nrf2, with the identification and verification of several potential drugs that can be applied in rescuing the decline of myogenin due to high P_i in muscle cells. Full article

(This article belongs to the Special Issue Epigenetic and Transcriptional Control of Skeletal Muscle Homeostasis, Regeneration, and Diseases)

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Review

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21 pages, 1967 KiB

Open AccessReview

Targeting Epigenetic Regulators with HDAC and BET Inhibitors to Modulate Muscle Wasting

by Lorenzo Nevi, Noora Pöllänen, Fabio Penna and Giuseppina Caretti

Int. J. Mol. Sci. 2023, 24(22), 16404; https://doi.org/10.3390/ijms242216404 - 16 Nov 2023

Cited by 1 | Viewed by 1821

Abstract

Epigenetic changes contribute to the profound alteration in the transcriptional program associated with the onset and progression of muscle wasting in several pathological conditions. Although HDACs and their inhibitors have been extensively studied in the field of muscular dystrophies, the potential of epigenetic inhibitors has only been marginally explored in other disorders associated with muscle atrophy, such as in cancer cachexia and sarcopenia. BET inhibitors represent a novel class of recently developed epigenetic drugs that display beneficial effects in a variety of diseases beyond malignancies. Based on the preliminary in vitro and preclinical data, HDACs and BET proteins contribute to the pathogenesis of cancer cachexia and sarcopenia, modulating processes related to skeletal muscle mass maintenance and/or metabolism. Thus, epigenetic drugs targeting HDACs and BET proteins may emerge as promising strategies to reverse the catabolic phenotype associated with cachexia and sarcopenia. Further preclinical studies are warranted to delve deeper into the molecular mechanisms associated with the functions of HDACs and BET proteins in muscle atrophy and to establish whether their epigenetic inhibitors represent a prospective therapeutic avenue to alleviate muscle wasting. Full article

(This article belongs to the Special Issue Epigenetic and Transcriptional Control of Skeletal Muscle Homeostasis, Regeneration, and Diseases)

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27 pages, 1728 KiB

Open AccessReview

Epitranscriptomics as a New Layer of Regulation of Gene Expression in Skeletal Muscle: Known Functions and Future Perspectives

by Carol Imbriano, Viviana Moresi, Silvia Belluti, Alessandra Renzini, Giorgia Cavioli, Eleonora Maretti and Susanna Molinari

Int. J. Mol. Sci. 2023, 24(20), 15161; https://doi.org/10.3390/ijms242015161 - 13 Oct 2023

Cited by 1 | Viewed by 1690

Abstract

Epitranscriptomics refers to post-transcriptional regulation of gene expression via RNA modifications and editing that affect RNA functions. Many kinds of modifications of mRNA have been described, among which are N6-methyladenosine (m6A), N1-methyladenosine (m1A), 7-methylguanosine (m7G), pseudouridine (Ψ), and 5-methylcytidine (m5C). They alter mRNA structure and consequently stability, localization and translation efficiency. Perturbation of the epitranscriptome is associated with human diseases, thus opening the opportunity for potential manipulations as a therapeutic approach. In this review, we aim to provide an overview of the functional roles of epitranscriptomic marks in the skeletal muscle system, in particular in embryonic myogenesis, muscle cell differentiation and muscle homeostasis processes. Further, we explored high-throughput epitranscriptome sequencing data to identify RNA chemical modifications in muscle-specific genes and we discuss the possible functional role and the potential therapeutic applications. Full article

(This article belongs to the Special Issue Epigenetic and Transcriptional Control of Skeletal Muscle Homeostasis, Regeneration, and Diseases)

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