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Mitochondrial Control of Muscle Growth in Health and Diseases
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Mitochondrial Control of Muscle Growth in Health and Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 18684

Special Issue Editor

Dr. B. Daan Westenbrink

E-Mail Website
Guest Editor
Department of Cardiology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
Interests: heart failure; mitochondria; ketones; mitophagy; calcium handling

Special Issue Information

Dear Colleagues,

The heart is the engine of life that relies on mitochondria for a continuous supply of energy. Mitochondria are unique multifunctional organelles that control a myriad of cellular responses including cardiac calcium handling, redox balance, and cell death. Recently, mitochondria have also been identified as key players in the regulation of pathological and physiological growth of striated muscle. Not only by providing the building blocks for growth, but also by fostering direct mitochondrial to nuclear crosstalk that regulate cellular growth responses. The exact mechanisms responsible for mitochondrial to nuclear crosstalk in cardiac and skeletal muscle and how they contribute to adaptive and maladaptive cardiac growth remains elusive. In the Special Issue, we solicit original and review articles that provide novel insights into the role of this intriguing form on subcellular communication in the context of adaptive and maladaptive muscle growth in health and disease.

Dr. B. Daan Westenbrink
Guest Editor

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Keywords

  • heart failure
  • mitochondria
  • mitochondrial unfolded protein response
  • calcium signaling
  • cardiac hypertrophy
  • physiological hypertrophy
  • ATP
  • exercise
  • ketone bodies
  • mitochondrial biogenesis
  • mitochondrial dynamics

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Published Papers (5 papers)

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Research

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19 pages, 7268 KiB  
Article
Selenoprotein DIO2 Is a Regulator of Mitochondrial Function, Morphology and UPRmt in Human Cardiomyocytes
by Nils Bomer, Mario G. Pavez-Giani, Frederik E. Deiman, Annet N. Linders, Martijn F. Hoes, Christiane L.J. Baierl, Silke U. Oberdorf-Maass, Rudolf A. de Boer, Herman H.W. Silljé, Eugene Berezikov, Warner S. Simonides, B. Daan Westenbrink and Peter van der Meer
Int. J. Mol. Sci. 2021, 22(21), 11906; https://doi.org/10.3390/ijms222111906 - 2 Nov 2021
Cited by 14 | Viewed by 3702
Abstract
Members of the fetal-gene-program may act as regulatory components to impede deleterious events occurring with cardiac remodeling, and constitute potential novel therapeutic heart failure (HF) targets. Mitochondrial energy derangements occur both during early fetal development and in patients with HF. Here we aim [...] Read more.
Members of the fetal-gene-program may act as regulatory components to impede deleterious events occurring with cardiac remodeling, and constitute potential novel therapeutic heart failure (HF) targets. Mitochondrial energy derangements occur both during early fetal development and in patients with HF. Here we aim to elucidate the role of DIO2, a member of the fetal-gene-program, in pluripotent stem cell (PSC)-derived human cardiomyocytes and on mitochondrial dynamics and energetics, specifically. RNA sequencing and pathway enrichment analysis was performed on mouse cardiac tissue at different time points during development, adult age, and ischemia-induced HF. To determine the function of DIO2 in cardiomyocytes, a stable human hPSC-line with a DIO2 knockdown was made using a short harpin sequence. Firstly, we showed the selenoprotein, type II deiodinase (DIO2): the enzyme responsible for the tissue-specific conversion of inactive (T4) into active thyroid hormone (T3), to be a member of the fetal-gene-program. Secondly, silencing DIO2 resulted in an increased reactive oxygen species, impaired activation of the mitochondrial unfolded protein response, severely impaired mitochondrial respiration and reduced cellular viability. Microscopical 3D reconstruction of the mitochondrial network displayed substantial mitochondrial fragmentation. Summarizing, we identified DIO2 to be a member of the fetal-gene-program and as a key regulator of mitochondrial performance in human cardiomyocytes. Our results suggest a key position of human DIO2 as a regulator of mitochondrial function in human cardiomyocytes. Full article
(This article belongs to the Special Issue Mitochondrial Control of Muscle Growth in Health and Diseases)
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18 pages, 3060 KiB  
Article
Ageing Causes Ultrastructural Modification to Calcium Release Units and Mitochondria in Cardiomyocytes
by Alessia Di Fonso, Laura Pietrangelo, Laura D’Onofrio, Antonio Michelucci, Simona Boncompagni and Feliciano Protasi
Int. J. Mol. Sci. 2021, 22(16), 8364; https://doi.org/10.3390/ijms22168364 - 4 Aug 2021
Cited by 6 | Viewed by 3155
Abstract
Ageing is associated with an increase in the incidence of heart failure, even if the existence of a real age-related cardiomyopathy remains controversial. Effective contraction and relaxation of cardiomyocytes depend on efficient production of ATP (handled by mitochondria) and on proper Ca2+ [...] Read more.
Ageing is associated with an increase in the incidence of heart failure, even if the existence of a real age-related cardiomyopathy remains controversial. Effective contraction and relaxation of cardiomyocytes depend on efficient production of ATP (handled by mitochondria) and on proper Ca2+ supply to myofibrils during excitation–contraction (EC) coupling (handled by Ca2+ release units, CRUs). Here, we analyzed mitochondria and CRUs in hearts of adult (4 months old) and aged (≥24 months old) mice. Analysis by confocal and electron microscopy (CM and EM, respectively) revealed an age-related loss of proper organization and disposition of both mitochondria and EC coupling units: (a) mitochondria are improperly disposed and often damaged (percentage of severely damaged mitochondria: adults 3.5 ± 1.1%; aged 16.5 ± 3.5%); (b) CRUs that are often misoriented (longitudinal) and/or misplaced from the correct position at the Z line. Immunolabeling with antibodies that mark either the SR or T-tubules indicates that in aged cardiomyocytes the sarcotubular system displays an extensive disarray. This disarray could be in part caused by the decreased expression of Cav-3 and JP-2 detected by western blot (WB), two proteins involved in formation of T-tubules and in docking SR to T-tubules in dyads. By WB analysis, we also detected increased levels of 3-NT in whole hearts homogenates of aged mice, a product of nitration of protein tyrosine residues, recognized as marker of oxidative stress. Finally, a detailed EM analysis of CRUs (formed by association of SR with T-tubules) points to ultrastructural modifications, i.e., a decrease in their frequency (adult: 5.1 ± 0.5; aged: 3.9 ± 0.4 n./50 μm2) and size (adult: 362 ± 40 nm; aged: 254 ± 60 nm). The changes in morphology and disposition of mitochondria and CRUs highlighted by our results may underlie an inefficient supply of Ca2+ ions and ATP to the contractile elements, and possibly contribute to cardiac dysfunction in ageing. Full article
(This article belongs to the Special Issue Mitochondrial Control of Muscle Growth in Health and Diseases)
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12 pages, 1725 KiB  
Article
Muscular and Molecular Pathology Associated with SPATA5 Deficiency in a Child with EHLMRS
by Frederik Braun, Andreas Hentschel, Albert Sickmann, Theodore Marteau, Swantje Hertel, Fabian Förster, Holger Prokisch, Matias Wagner, Saskia Wortmann, Adela Della Marina, Heike Kölbel, Andreas Roos and Ulrike Schara-Schmidt
Int. J. Mol. Sci. 2021, 22(15), 7835; https://doi.org/10.3390/ijms22157835 - 22 Jul 2021
Cited by 4 | Viewed by 3398
Abstract
Mutations in the SPATA5 gene are associated with epilepsy, hearing loss and mental retardation syndrome (EHLMRS). While SPATA5 is ubiquitously expressed and is attributed a role within mitochondrial morphogenesis during spermatogenesis, there is only limited knowledge about the associated muscular and molecular pathology. [...] Read more.
Mutations in the SPATA5 gene are associated with epilepsy, hearing loss and mental retardation syndrome (EHLMRS). While SPATA5 is ubiquitously expressed and is attributed a role within mitochondrial morphogenesis during spermatogenesis, there is only limited knowledge about the associated muscular and molecular pathology. This study reports on a comprehensive workup of muscular pathology, including proteomic profiling and microscopic studies, performed on an 8-year-old girl with typical clinical presentation of EHLMRS, where exome analysis revealed two clinically relevant, compound-heterozygous variants in SPATA5. Proteomic profiling of a quadriceps biopsy showed the dysregulation of 82 proteins, out of which 15 were localized in the mitochondrion, while 19 were associated with diseases presenting with phenotypical overlap to EHLMRS. Histological staining of our patient’s muscle biopsy hints towards mitochondrial pathology, while the identification of dysregulated proteins attested to the vulnerability of the cell beyond the mitochondria. Through our study we provide insights into the molecular etiology of EHLMRS and provide further evidence for a muscle pathology associated with SPATA5 deficiency, including a pathological histochemical pattern accompanied by dysregulated protein expression. Full article
(This article belongs to the Special Issue Mitochondrial Control of Muscle Growth in Health and Diseases)
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20 pages, 4025 KiB  
Article
ATPase Inhibitory Factor-1 Disrupts Mitochondrial Ca2+ Handling and Promotes Pathological Cardiac Hypertrophy through CaMKIIδ
by Mario G. Pavez-Giani, Pablo I. Sánchez-Aguilera, Nils Bomer, Shigeki Miyamoto, Harmen G. Booij, Paula Giraldo, Silke U. Oberdorf-Maass, Kirsten T. Nijholt, Salva R. Yurista, Hendrik Milting, Peter van der Meer, Rudolf A. de Boer, Joan Heller Brown, Herman W. H. Sillje and B. Daan Westenbrink
Int. J. Mol. Sci. 2021, 22(9), 4427; https://doi.org/10.3390/ijms22094427 - 23 Apr 2021
Cited by 10 | Viewed by 3818
Abstract
ATPase inhibitory factor-1 (IF1) preserves cellular ATP under conditions of respiratory collapse, yet the function of IF1 under normal respiring conditions is unresolved. We tested the hypothesis that IF1 promotes mitochondrial dysfunction and pathological cardiomyocyte hypertrophy in the context of heart failure (HF). [...] Read more.
ATPase inhibitory factor-1 (IF1) preserves cellular ATP under conditions of respiratory collapse, yet the function of IF1 under normal respiring conditions is unresolved. We tested the hypothesis that IF1 promotes mitochondrial dysfunction and pathological cardiomyocyte hypertrophy in the context of heart failure (HF). Methods and results: Cardiac expression of IF1 was increased in mice and in humans with HF, downstream of neurohumoral signaling pathways and in patterns that resembled the fetal-like gene program. Adenoviral expression of wild-type IF1 in primary cardiomyocytes resulted in pathological hypertrophy and metabolic remodeling as evidenced by enhanced mitochondrial oxidative stress, reduced mitochondrial respiratory capacity, and the augmentation of extramitochondrial glycolysis. Similar perturbations were observed with an IF1 mutant incapable of binding to ATP synthase (E55A mutation), an indication that these effects occurred independent of binding to ATP synthase. Instead, IF1 promoted mitochondrial fragmentation and compromised mitochondrial Ca2+ handling, which resulted in sarcoplasmic reticulum Ca2+ overloading. The effects of IF1 on Ca2+ handling were associated with the cytosolic activation of calcium–calmodulin kinase II (CaMKII) and inhibition of CaMKII or co-expression of catalytically dead CaMKIIδC was sufficient to prevent IF1 induced pathological hypertrophy. Conclusions: IF1 represents a novel member of the fetal-like gene program that contributes to mitochondrial dysfunction and pathological cardiac remodeling in HF. Furthermore, we present evidence for a novel, ATP-synthase-independent, role for IF1 in mitochondrial Ca2+ handling and mitochondrial-to-nuclear crosstalk involving CaMKII. Full article
(This article belongs to the Special Issue Mitochondrial Control of Muscle Growth in Health and Diseases)
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Review

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19 pages, 866 KiB  
Review
Skeletal Muscle Mitochondria Dysfunction in Genetic Neuromuscular Disorders with Cardiac Phenotype
by Elena Ignatieva, Natalia Smolina, Anna Kostareva and Renata Dmitrieva
Int. J. Mol. Sci. 2021, 22(14), 7349; https://doi.org/10.3390/ijms22147349 - 8 Jul 2021
Cited by 14 | Viewed by 3687
Abstract
Mitochondrial dysfunction is considered the major contributor to skeletal muscle wasting in different conditions. Genetically determined neuromuscular disorders occur as a result of mutations in the structural proteins of striated muscle cells and therefore are often combined with cardiac phenotype, which most often [...] Read more.
Mitochondrial dysfunction is considered the major contributor to skeletal muscle wasting in different conditions. Genetically determined neuromuscular disorders occur as a result of mutations in the structural proteins of striated muscle cells and therefore are often combined with cardiac phenotype, which most often manifests as a cardiomyopathy. The specific roles played by mitochondria and mitochondrial energetic metabolism in skeletal muscle under muscle-wasting conditions in cardiomyopathies have not yet been investigated in detail, and this aspect of genetic muscle diseases remains poorly characterized. This review will highlight dysregulation of mitochondrial representation and bioenergetics in specific skeletal muscle disorders caused by mutations that disrupt the structural and functional integrity of muscle cells. Full article
(This article belongs to the Special Issue Mitochondrial Control of Muscle Growth in Health and Diseases)
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