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Molecular Basis and Translational Research in Metabolic Myopathies: A Themed...
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Molecular Basis and Translational Research in Metabolic Myopathies: A Themed Issue in Honor of Professor Corrado Angelini

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 30 June 2024 | Viewed by 11589

Special Issue Editors

Dr. Marija Meznaric

E-Mail Website
Guest Editor
Institute of Anatomy, Faculty of Medicine, University of Ljubljana, Korytkova 2, 1000 Ljubljana, Slovenia
Interests: neuromuscular diseases; muscular dystrophies; metabolic myopathies; protein expression; muscle biopsy
Prof. Dr. Daniela Tavian

E-Mail Website
Guest Editor
Department of Psychology, Catholic University, 20123 Milan, Italy
Interests: NLSD-M; NLSD-I
Special Issues, Collections and Topics in MDPI journals
Dr. Sara Missaglia

E-Mail Website
Guest Editor
Laboratory of Cellular Biochemistry and Molecular Biology, Catholic University of the Sacred Heart, 20145 Milan, Italy
Interests: lipid metabolism; neutral lipid storage disease; human genetics; cellular biochemistry; molecular biology

Special Issue Information

Dear Colleagues, 

Metabolic myopathies are genetic disorders regarding the utilization of carbohydrates or fat in muscles. Glycogen-storage diseases and fatty acid transport and oxidation defects represent two of the main classes of these defects.  In some, the acute nature of energy failure is manifested by a metabolic crisis with muscle weakness, cramps, myalgias sometimes associated by myoglobinuria with normal interictal examination. A typical disorder where permanent muscle weakness occurs is glycogenosis type II (GSDII) or Pompe disease. Pompe disease is caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA) due to different mutations in infantile and late onset Pompe disease. Enzyme replacement therapy (ERT) with recombinant human alpha-glucosidase has led to improvement of cardiac function in infants, although there is still central nervous system impairment, since the recombinant GAA does not cross the blood–brain barrier. A new preparation of ERT using recombinant GAA enriched with mannose and the concomitant use of chaperons is currently under study. Danon disease is a rare cardiac and skeletal muscle disorder caused by lysosome-associated membrane protein 2 mutations and presenting with systemic symptoms of cardiomyopathy, skeletal myopathy, and intellectual disability. Pompe and Danon disease are two autophagic vacuolar myopathies, that are characterized by the presence of large glycogen-filled lysosomes in the skeletal muscle. While autophagy impairment contributes to disease progression in GSD2 and Danon disease, the mechanism that leads to autophagy inhibition remains unknown. Reactivation of autophagy in Pompe patients by exercise and other signalling factors is a possible therapeutic action to ameliorate the long standing glycogen deposition. Secondary events such as dysregulation of calcium homeostasis, oxidative stress and mitochondrial abnormalities all may contribute to tissue damage in lysosomal storage diseases.

The pathogenetic mechanism of muscle impairment is completely unknown for some metabolic myopathies, e.g.,  Neutral Lipid Storage Disease with Myopathy and Neutral Lipid Storage Disease with Ichthyosis and, for this reason, drug therapy is not available yet. 

The Special Issue “Molecular basis and translational research in metabolic myopathies: a themed issue in honour of Professor Corrado Angelini” aims to highlight recent advances in our understanding of preclinical and clinical knowledge on the mechanisms of disease pathogenesis and progression in glycogen-storage and lipid-storage myopathies with the aim to discover the most critical pathways and how to reactivate them in order to optimise treatment and stop disease progression. This Special Issue of Biomolecules will focus on novel findings on the molecular players and mechanisms involved in pathophysiology of glycogen and lipid metabolic myopathies. This will include experimental studies in animal models and innovative cellular models, like induced pluripotent stem cells (iPSCs) and also specific therapeutic treatments. Novel diagnostic tools and dietary or innovative strategies on characterizing gene expressions involved in such diseases are welcome.

We look forward to receiving your contribution.

Dr. Marija Meznaric
Prof. Dr. Daniela Tavian
Dr. Sara Missaglia
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • metabolic myopathies
  • lipid metabolism
  • glycogen metabolism
  • genetic diseases
  • treatments
  • lipid storage myopathies
  • glycogen storage myopathies
  • lysosomal storage myopathies

Published Papers (6 papers)

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Research

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12 pages, 2491 KiB  
Article
Effects of Triheptanoin on Mitochondrial Respiration and Glycolysis in Cultured Fibroblasts from Neutral Lipid Storage Disease Type M (NLSD-M) Patients
by Nelida Inés Noguera, Daniela Tavian, Corrado Angelini, Francesca Cortese, Massimiliano Filosto, Matteo Garibaldi, Sara Missaglia, Ariela Smigliani, Alessandra Zaza and Elena Maria Pennisi
Biomolecules 2023, 13(3), 452; https://doi.org/10.3390/biom13030452 - 01 Mar 2023
Cited by 1 | Viewed by 2013
Abstract
Neutral lipid storage disease type M (NLSD-M) is an ultra-rare, autosomal recessive disorder that causes severe skeletal and cardiac muscle damage and lipid accumulation in all body tissues. In this hereditary pathology, the defective action of the adipose triglyceride lipase (ATGL) enzyme induces [...] Read more.
Neutral lipid storage disease type M (NLSD-M) is an ultra-rare, autosomal recessive disorder that causes severe skeletal and cardiac muscle damage and lipid accumulation in all body tissues. In this hereditary pathology, the defective action of the adipose triglyceride lipase (ATGL) enzyme induces the enlargement of cytoplasmic lipid droplets and reduction in the detachment of mono- (MG) and diglycerides (DG). Although the pathogenesis of muscle fiber necrosis is unknown, some studies have shown alterations in cellular energy production, probably because MG and DG, the substrates of Krebs cycle, are less available. No tests have been tried with medium-chain fatty acid molecules to evaluate the anaplerotic effect in NLSD cells. In this study, we evaluated the in vitro effect of triheptanoin (Dojolvi®), a highly purified chemical triglyceride with seven carbon atoms, in fibroblasts obtained from five NLSD-M patients. Glycolytic and mitochondrial functions were determined by Seahorse XF Agylent Technology, and cellular viability and triglyceride content were measured through colorimetric assays. After the addition of triheptanoin, we observed an increase in glycolysis and mitochondrial respiration in all patients compared with healthy controls. These preliminary results show that triheptanoin is able to induce an anaplerotic effect in NLSD-M fibroblasts, paving the way towards new therapeutic strategies. Full article
(This article belongs to the Special Issue Molecular Basis and Translational Research in Metabolic Myopathies: A Themed Issue in Honor of Professor Corrado Angelini)
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Review

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14 pages, 679 KiB  
Review
Biomolecules of Muscle Fatigue in Metabolic Myopathies
by Erika Schirinzi, Giulia Ricci, Francesca Torri, Michelangelo Mancuso and Gabriele Siciliano
Biomolecules 2024, 14(1), 50; https://doi.org/10.3390/biom14010050 - 30 Dec 2023
Cited by 1 | Viewed by 1460
Abstract
Metabolic myopathies are a group of genetic disorders that affect the normal functioning of muscles due to abnormalities in metabolic pathways. These conditions result in impaired energy production and utilization within muscle cells, leading to limitations in muscle function with concomitant occurrence of [...] Read more.
Metabolic myopathies are a group of genetic disorders that affect the normal functioning of muscles due to abnormalities in metabolic pathways. These conditions result in impaired energy production and utilization within muscle cells, leading to limitations in muscle function with concomitant occurrence of related signs and symptoms, among which fatigue is one of the most frequently reported. Understanding the underlying molecular mechanisms of muscle fatigue in these conditions is challenging for the development of an effective diagnostic and prognostic approach to test targeted therapeutic interventions. This paper outlines the key biomolecules involved in muscle fatigue in metabolic myopathies, including energy substrates, enzymes, ion channels, and signaling molecules. Potential future research directions in this field are also discussed. Full article
(This article belongs to the Special Issue Molecular Basis and Translational Research in Metabolic Myopathies: A Themed Issue in Honor of Professor Corrado Angelini)
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21 pages, 526 KiB  
Review
Are Anti-rhGAA Antibodies a Determinant of Treatment Outcome in Adults with Late-Onset Pompe Disease? A Systematic Review
by Imke A. M. Ditters, Harmke A. van Kooten, Nadine A. M. E. van der Beek, Ans T. van der Ploeg, Hidde H. Huidekoper and Johanna M. P. van den Hout
Biomolecules 2023, 13(9), 1414; https://doi.org/10.3390/biom13091414 - 19 Sep 2023
Viewed by 1259
Abstract
Background: Pompe disease is a lysosomal storage disease characterised by skeletal and respiratory muscle weakness. Since 2006, enzyme replacement therapy (ERT) with alglucosidase alfa has been available. ERT significantly improves the prognosis of patients with Pompe disease. The effect of high antibody titres [...] Read more.
Background: Pompe disease is a lysosomal storage disease characterised by skeletal and respiratory muscle weakness. Since 2006, enzyme replacement therapy (ERT) with alglucosidase alfa has been available. ERT significantly improves the prognosis of patients with Pompe disease. The effect of high antibody titres on treatment response in adults with late-onset Pompe disease (LOPD) remains unclear but may contribute to interpatient variation. We therefore conducted a systematic review on this subject. Methods: A systematic search was performed in Embase, Medline Ovid, Web of Science, Psych Info Ovid, Cochrane (Clinical Trials only), and Google Scholar (random top-200). Articles were included if they involved adults with LOPD treated with alglucosidase alfa and mentioned anti-rhGAA antibodies or antibody titres. In addition, articles mentioning dosages different from the standard recommended dosage were included. Results: Our literature search retrieved 2562 publications, and 17 fulfilled our selection criteria, describing 443 cases. Seven publications reported on anti-rhGAA antibody titres on a group level, with the percentage of patients with a high titre as defined in the included articles ranging from 0–33%. Six publications reported on the effect of anti-rhGAA antibody titre on clinical course, and four found no correlation. Two studies reported a negative effect on treatment. The first study found a greater improvement in Medical Research Council (MRC) score in patients with no detectable antibody titre. In the second study, a patient discontinued ERT due to a declining neuromuscular state as a result of high anti-rhGAA antibody titres. Seven publications reported on 17 individual patients with a high antibody titre (range 1:12,800–1:3,906,250). In only two cases were high-sustained neutralising antibodies reported to interfere with treatment efficacy. Conclusions: No clear effect of anti-rhGAA IgG antibodies on treatment response could be established for the majority of LOPD patients with a high antibody titre. In a minority of patients, a clinical decline related to (possible) interference of anti-rhGAA antibodies was described. Full article
(This article belongs to the Special Issue Molecular Basis and Translational Research in Metabolic Myopathies: A Themed Issue in Honor of Professor Corrado Angelini)
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14 pages, 813 KiB  
Review
Advances in Dystrophinopathy Diagnosis and Therapy
by Fawzy A. Saad, Gabriele Siciliano and Corrado Angelini
Biomolecules 2023, 13(9), 1319; https://doi.org/10.3390/biom13091319 - 28 Aug 2023
Cited by 5 | Viewed by 2834
Abstract
Dystrophinopathies are x-linked muscular disorders which emerge from mutations in the Dystrophin gene, including Duchenne and Becker muscular dystrophy, and dilated cardiomyopathy. However, Duchenne muscular dystrophy interconnects with bone loss and osteoporosis, which are exacerbated by glucocorticoids therapy. Procedures for diagnosing dystrophinopathies include [...] Read more.
Dystrophinopathies are x-linked muscular disorders which emerge from mutations in the Dystrophin gene, including Duchenne and Becker muscular dystrophy, and dilated cardiomyopathy. However, Duchenne muscular dystrophy interconnects with bone loss and osteoporosis, which are exacerbated by glucocorticoids therapy. Procedures for diagnosing dystrophinopathies include creatine kinase assay, haplotype analysis, Southern blot analysis, immunological analysis, multiplex PCR, multiplex ligation-dependent probe amplification, Sanger DNA sequencing, and next generation DNA sequencing. Pharmacological therapy for dystrophinopathies comprises glucocorticoids (prednisone, prednisolone, and deflazacort), vamorolone, and ataluren. However, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and β-blockers are the first-line to prevent dilated cardiomyopathy in dystrophinopathy patients. Duchenne muscular dystrophy gene therapy strategies involve gene transfer, exon skipping, exon reframing, and CRISPR gene editing. Eteplirsen, an antisense-oligonucleotide drug for skipping exon 51 from the Dystrophin gene, is available on the market, which may help up to 14% of Duchenne muscular dystrophy patients. There are various FDA-approved exon skipping drugs including ExonDys-51 for exon 51, VyonDys-53 and Viltolarsen for exon 53 and AmonDys-45 for exon 45 skipping. Other antisense oligonucleotide drugs in the pipeline include casimersen for exon 45, suvodirsen for exon 51, and golodirsen for exon 53 skipping. Advances in the diagnosis and therapy of dystrophinopathies offer new perspectives for their early discovery and care. Full article
(This article belongs to the Special Issue Molecular Basis and Translational Research in Metabolic Myopathies: A Themed Issue in Honor of Professor Corrado Angelini)
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26 pages, 848 KiB  
Review
A Comprehensive Update on Late-Onset Pompe Disease
by Beatrice Labella, Stefano Cotti Piccinelli, Barbara Risi, Filomena Caria, Simona Damioli, Enrica Bertella, Loris Poli, Alessandro Padovani and Massimiliano Filosto
Biomolecules 2023, 13(9), 1279; https://doi.org/10.3390/biom13091279 - 22 Aug 2023
Cited by 1 | Viewed by 2626
Abstract
Pompe disease (PD) is an autosomal recessive disorder caused by mutations in the GAA gene that lead to a deficiency in the acid alpha-glucosidase enzyme. Two clinical presentations are usually considered, named infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD), which differ [...] Read more.
Pompe disease (PD) is an autosomal recessive disorder caused by mutations in the GAA gene that lead to a deficiency in the acid alpha-glucosidase enzyme. Two clinical presentations are usually considered, named infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD), which differ in age of onset, organ involvement, and severity of disease. Assessment of acid alpha-glucosidase activity on a dried blood spot is the first-line screening test, which needs to be confirmed by genetic analysis in case of suspected deficiency. LOPD is a multi-system disease, thus requiring a multidisciplinary approach for efficacious management. Enzyme replacement therapy (ERT), which was introduced over 15 years ago, changes the natural progression of the disease. However, it has limitations, including a reduction in efficacy over time and heterogeneous therapeutic responses among patients. Novel therapeutic approaches, such as gene therapy, are currently under study. We provide a comprehensive review of diagnostic advances in LOPD and a critical discussion about the advantages and limitations of current and future treatments. Full article
(This article belongs to the Special Issue Molecular Basis and Translational Research in Metabolic Myopathies: A Themed Issue in Honor of Professor Corrado Angelini)
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Other

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17 pages, 3243 KiB  
Case Report
Phenotypic Variability of Andersen–Tawil Syndrome Due to Allelic Mutation c.652C>T in the KCNJ2 Gene—A New Family Case Report
by Maria Elena Onore, Esther Picillo, Paola D’Ambrosio, Salvatore Morra, Vincenzo Nigro and Luisa Politano
Biomolecules 2024, 14(4), 507; https://doi.org/10.3390/biom14040507 - 22 Apr 2024
Viewed by 294
Abstract
Andersen–Tawil syndrome (ATS) is a multisystem channelopathy characterized by periodic paralysis, ventricular arrhythmias, prolonged QT interval, and facial dysmorphisms occurring in the first/second decade of life. High phenotypic variability and incomplete penetrance of the genes causing the disease make its diagnosis still a [...] Read more.
Andersen–Tawil syndrome (ATS) is a multisystem channelopathy characterized by periodic paralysis, ventricular arrhythmias, prolonged QT interval, and facial dysmorphisms occurring in the first/second decade of life. High phenotypic variability and incomplete penetrance of the genes causing the disease make its diagnosis still a challenge. We describe a three-generation family with six living individuals affected by ATS. The proband is a 37-year-old woman presenting since age 16, with episodes of muscle weakness and cramps in the pre-menstrual period. The father, two brothers, one paternal uncle and one cousin also complained of cramps, muscle stiffness, and weakness. Despite normal serum potassium concentration, treatment with potassium, magnesium, and acetazolamide alleviated paralysis attacks suggesting a dyskalemic syndrome. Dysmorphic features were noted in the proband, only later. On the ECG, all but one had normal QT intervals. The affected males developed metabolic syndrome or obesity. The father had two myocardial infarctions and was implanted with an intracardiac cardioverter defibrillator (ICD). A genetic investigation by WES analysis detected the heterozygous pathogenic variant (NM_000891.2: c.652C>T, p. Arg218Trp) in the KCNJ2 gene related to ATS, confirmed by segregation studies in all affected members. Furthermore, we performed a review of cases with the same mutation in the literature, looking for similarities and divergences with our family case. Full article
(This article belongs to the Special Issue Molecular Basis and Translational Research in Metabolic Myopathies: A Themed Issue in Honor of Professor Corrado Angelini)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Biomolecules of muscle fatigiue in Metabolic Myopathies
Authors: Gabriele Siciliano, Francesca Torri, Erika Schirinzi, Giulia Ricci,
Affiliation: University of Pisa, Pisa (I)

Title: History and perspective of LAMP-2 deficiency （Danon disease）
Authors: Kazuma Sugie and Ichizo Nishino
Affiliation: National Institute of Neuroscience, National Center of Neurology and Psychiatry（NCNP）, 4-1-1 ogawahigashi-cho, Kodaira, Tokyo 187-8502, Japan

Title: Failure of autophagy in Pompe disease
Authors: Hung Do, Naresh K. Meena, Nina Raben
Affiliation: M6P Therapeutics, St. Louis, MO

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