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Highlights in Pathophysiology of the Musculoskeletal System

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 (31 October 2022) | Viewed by 49319

Special Issue Editors

Dr. Marta Anna Szychlinska

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Guest Editor
Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), Human Anatomy Section, University of Palermo, 90127 Palermo, Italy
Interests: articular cartilage engineering; chondrogenesis; mesenchymal stem cells; aging; hypertrophy; morphology; pathophysiology; osteoarthritis
Special Issues, Collections and Topics in MDPI journals
Dr. Rosario Barone

E-Mail Website
Guest Editor
Department of Biomedicine, Neuroscience and Advanced Diagnostics, Institute of Human Anatomy and Histology, University of Palermo, 90133 Palermo, Italy
Interests: cell biology; physiology; exercise performance; nutition; sports science; morphology; pathopysiology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

The musculoskeletal system is an organ system that provides support, shape, and stability, and enables the movement of joints in the human body. It mainly consists of bones, skeletal muscles, tendons, ligaments, intervertebral discs, and articular cartilage tissue, as well as their associated nerves and blood vessels. Due to their primary functions, they are by far the most commonly injured tissues in the body, and musculoskeletal disorders represent one of the most common health problems worldwide. During the past few decades, with the advancement of research and technology, much has been discovered concerning the pathophysiological knowledge of the musculoskeletal system. Novel molecular targets have been identified for therapeutic approaches. Innovative methodologies such as tissue engineering, regenerative medicine, gene therapies, drug delivery systems, microgravity conditions, and nutritional interventions have facilitated the development of understanding mechanisms of musculoskeletal disorders such as osteoarthritis, rheumatoid arthritis, sarcopenia, muscle wasting, osteoporosis, bone necrosis, and many others.

In this Special Issue of the International Journal of Molecular Sciences, we focus our attention on the latest discoveries and developments in musculoskeletal system pathophysiology at a molecular level and provide a comprehensive update on the literature accessible to scientists from the field. Thus, we wish to invite investigators from basic, pathophysiological, and translational musculoskeletal system research or closely related disciplines to contribute original articles, reviews, communications, and conceptual papers.

.

Dr. Marta Anna Szychlinska
Dr. Rosario Barone
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • musculoskeletal

  • skeletal
  • tendon
  • ligament
  • intervertebral
  • articular cartilage
  • osteoarthritis
  • rheumatoid arthritis
  • sarcopenia
  • muscle wasting
  • osteoporosis
  • bone necrosis
  • synovium
  • pain
  • inflammation

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Published Papers (18 papers)

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Editorial

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5 pages, 218 KiB  
Editorial
Highlights in Pathophysiology of the Musculoskeletal System
by Rosario Barone and Marta A. Szychlinska
Int. J. Mol. Sci. 2023, 24(7), 6412; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076412 - 29 Mar 2023
Cited by 1 | Viewed by 1525
Abstract
The intention of the present Special Issue is to focus on the latest research in the musculoskeletal system, with an emphasis on the molecular mechanisms underlying its pathophysiology, as well as innovative diagnostic tools and therapeutic perspectives [...] Full article
(This article belongs to the Special Issue Highlights in Pathophysiology of the Musculoskeletal System)

Research

Jump to: Editorial, Review

13 pages, 3957 KiB  
Article
Elevated Expression of ADAM10 in Skeletal Muscle of Patients with Idiopathic Inflammatory Myopathies Could Be Responsible for FNDC5/Irisin Unbalance
by Roberta Zerlotin, Marco Fornaro, Mariella Errede, Patrizia Pignataro, Clelia Suriano, Maddalena Ruggieri, Silvia Colucci, Florenzo Iannone, Maria Grano and Graziana Colaianni
Int. J. Mol. Sci. 2023, 24(3), 2469; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032469 - 27 Jan 2023
Cited by 2 | Viewed by 1579
Abstract
Dermatomyositis (DM) and immune-mediated necrotizing myopathy (IMNM) are two rare diseases belonging to the group of idiopathic inflammatory myopathies (IIM). Muscle involvement in DM is characterized by perifascicular atrophy and poor myofiber necrosis, while IMNM is characterized by myofiber necrosis with scarce inflammatory [...] Read more.
Dermatomyositis (DM) and immune-mediated necrotizing myopathy (IMNM) are two rare diseases belonging to the group of idiopathic inflammatory myopathies (IIM). Muscle involvement in DM is characterized by perifascicular atrophy and poor myofiber necrosis, while IMNM is characterized by myofiber necrosis with scarce inflammatory infiltrates. Muscle biopsies and laboratory tests are helpful in diagnosis, but currently, few biomarkers of disease activity and progression are available. In this context, we conducted a cohort study of forty-one DM and IMNM patients, aged 40–70 years. In comparison with control subjects, in the muscle biopsies of these patients, there was a lower expression of FNDC5, the precursor of irisin, a myokine playing a key role in musculoskeletal metabolism. Expectedly, the muscle cross-sectional areas of these patients were reduced, while, surprisingly, serum irisin levels were higher than in CTRL, as were mRNA levels of ADAM10, a metalloproteinase recently shown to be the cleavage agent for FNDC5. We hypothesize that elevated expression of ADAM10 in the skeletal muscle of DM and IMNM patients might be responsible for the discrepancy between irisin levels and FNDC5 expression. Future studies will be needed to understand the mechanisms underlying exacerbated FNDC5 cleavage and muscle irisin resistance in these inflammatory myopathies. Full article
(This article belongs to the Special Issue Highlights in Pathophysiology of the Musculoskeletal System)
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20 pages, 3754 KiB  
Article
Episodic Binge-like Ethanol Reduces Skeletal Muscle Strength Associated with Atrophy, Fibrosis, and Inflammation in Young Rats
by Constanza Cáceres-Ayala, Rodrigo G. Mira, María José Acuña, Enrique Brandan, Waldo Cerpa and Daniela L. Rebolledo
Int. J. Mol. Sci. 2023, 24(2), 1655; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24021655 - 14 Jan 2023
Cited by 4 | Viewed by 1802
Abstract
Binge Drinking (BD) corresponds to episodes of ingestion of large amounts of ethanol in a short time, typically ≤2 h. BD occurs across all populations, but young and sports-related people are especially vulnerable. However, the short- and long-term effects of episodic BD on [...] Read more.
Binge Drinking (BD) corresponds to episodes of ingestion of large amounts of ethanol in a short time, typically ≤2 h. BD occurs across all populations, but young and sports-related people are especially vulnerable. However, the short- and long-term effects of episodic BD on skeletal muscle function have been poorly explored. Young rats were randomized into two groups: control and episodic Binge-Like ethanol protocol (BEP) (ethanol 3 g/kg IP, 4 episodes of 2-days ON-2-days OFF paradigm). Muscle function was evaluated two weeks after the last BEP episode. We found that rats exposed to BEP presented decreased muscle strength and increased fatigability, compared with control animals. Furthermore, we observed that skeletal muscle from rats exposed to BEP presented muscle atrophy, evidenced by reduced fiber size and increased expression of atrophic genes. We also observed that BEP induced fibrotic and inflammation markers, accompanied by mislocalization of nNOSµ and high levels of protein nitration. Our findings suggest that episodic binge-like ethanol exposure alters contractile capacity and increases fatigue by mechanisms involving atrophy, fibrosis, and inflammation, which remain for at least two weeks after ethanol clearance. These pathological features are common to several neuromuscular diseases and might affect muscle performance and health in the long term. Full article
(This article belongs to the Special Issue Highlights in Pathophysiology of the Musculoskeletal System)
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16 pages, 4616 KiB  
Article
Evaluation of Sodium Relaxation Times and Concentrations in the Achilles Tendon Using MRI
by Benedikt Kamp, Miriam Frenken, Lena Klein-Schmeink, Armin M. Nagel, Lena M. Wilms, Karl Ludger Radke, Styliani Tsiami, Philipp Sewerin, Xenofon Baraliakos, Gerald Antoch, Daniel B. Abrar, Hans-Jörg Wittsack and Anja Müller-Lutz
Int. J. Mol. Sci. 2022, 23(18), 10890; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810890 - 17 Sep 2022
Cited by 4 | Viewed by 1531
Abstract
Sodium magnetic resonance imaging (MRI) can be used to evaluate the change in the proteoglycan content in Achilles tendons (ATs) of patients with different AT pathologies by measuring the 23Na signal-to-noise ratio (SNR). As 23Na SNR alone is difficult to compare [...] Read more.
Sodium magnetic resonance imaging (MRI) can be used to evaluate the change in the proteoglycan content in Achilles tendons (ATs) of patients with different AT pathologies by measuring the 23Na signal-to-noise ratio (SNR). As 23Na SNR alone is difficult to compare between different studies, because of the high influence of hardware configurations and sequence settings on the SNR, we further set out to measure the apparent tissue sodium content (aTSC) in the AT as a better comparable parameter. Ten healthy controls and one patient with tendinopathy in the AT were examined using a clinical 3 Tesla (T) MRI scanner in conjunction with a dual tuned 1H/23Na surface coil to measure 23Na SNR and aTSC in their ATs. 23Na T1 and T2* of the AT were also measured for three controls to correct for different relaxation behavior. The results were as follows: 23Na SNR = 11.7 ± 2.2, aTSC = 82.2 ± 13.9 mM, 23Na T1 = 20.4 ± 2.4 ms, 23Na T2s* = 1.4 ± 0.4 ms, and 23Na T2l* = 13.9 ± 0.8 ms for the whole AT of healthy controls with significant regional differences. These are the first reported aTSCs and 23Na relaxation times for the AT using sodium MRI and may serve for future comparability in different studies regarding examinations of diseased ATs with sodium MRI. Full article
(This article belongs to the Special Issue Highlights in Pathophysiology of the Musculoskeletal System)
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17 pages, 1872 KiB  
Article
Gain-of-Function Dynamin-2 Mutations Linked to Centronuclear Myopathy Impair Ca2+-Induced Exocytosis in Human Myoblasts
by Lucas Bayonés, María José Guerra-Fernández, Fernando Hinostroza, Ximena Báez-Matus, Jacqueline Vásquez-Navarrete, Luciana I. Gallo, Sergio Parra, Agustín D. Martínez, Arlek González-Jamett, Fernando D. Marengo and Ana M. Cárdenas
Int. J. Mol. Sci. 2022, 23(18), 10363; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810363 - 08 Sep 2022
Cited by 1 | Viewed by 1756
Abstract
Gain-of-function mutations of dynamin-2, a mechano-GTPase that remodels membrane and actin filaments, cause centronuclear myopathy (CNM), a congenital disease that mainly affects skeletal muscle tissue. Among these mutations, the variants p.A618T and p.S619L lead to a gain of function and cause a severe [...] Read more.
Gain-of-function mutations of dynamin-2, a mechano-GTPase that remodels membrane and actin filaments, cause centronuclear myopathy (CNM), a congenital disease that mainly affects skeletal muscle tissue. Among these mutations, the variants p.A618T and p.S619L lead to a gain of function and cause a severe neonatal phenotype. By using total internal reflection fluorescence microscopy (TIRFM) in immortalized human myoblasts expressing the pH-sensitive fluorescent protein (pHluorin) fused to the insulin-responsive aminopeptidase IRAP as a reporter of the GLUT4 vesicle trafficking, we measured single pHluorin signals to investigate how p.A618T and p.S619L mutations influence exocytosis. We show here that both dynamin-2 mutations significantly reduced the number and durations of pHluorin signals induced by 10 μM ionomycin, indicating that in addition to impairing exocytosis, they also affect the fusion pore dynamics. These mutations also disrupt the formation of actin filaments, a process that reportedly favors exocytosis. This altered exocytosis might importantly disturb the plasmalemma expression of functional proteins such as the glucose transporter GLUT4 in skeletal muscle cells, impacting the physiology of the skeletal muscle tissue and contributing to the CNM disease. Full article
(This article belongs to the Special Issue Highlights in Pathophysiology of the Musculoskeletal System)
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17 pages, 4601 KiB  
Article
Characterisation of Progressive Skeletal Muscle Fibrosis in the Mdx Mouse Model of Duchenne Muscular Dystrophy: An In Vivo and In Vitro Study
by Matteo Giovarelli, Francesca Arnaboldi, Silvia Zecchini, Laura Brigida Cornaghi, Ambra Nava, Michele Sommariva, Emilio Giuseppe Ignazio Clementi and Nicoletta Gagliano
Int. J. Mol. Sci. 2022, 23(15), 8735; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158735 - 05 Aug 2022
Cited by 10 | Viewed by 3176
Abstract
Duchenne muscular dystrophy (DMD) is a rare genetic disease leading to progressive muscle wasting, respiratory failure, and cardiomyopathy. Although muscle fibrosis represents a DMD hallmark, the organisation of the extracellular matrix and the molecular changes in its turnover are still not fully understood. [...] Read more.
Duchenne muscular dystrophy (DMD) is a rare genetic disease leading to progressive muscle wasting, respiratory failure, and cardiomyopathy. Although muscle fibrosis represents a DMD hallmark, the organisation of the extracellular matrix and the molecular changes in its turnover are still not fully understood. To define the architectural changes over time in muscle fibrosis, we used an mdx mouse model of DMD and analysed collagen and glycosaminoglycans/proteoglycans content in skeletal muscle sections at different time points during disease progression and in comparison with age-matched controls. Collagen significantly increased particularly in the diaphragm, quadriceps, and gastrocnemius in adult mdx, with fibrosis significantly correlating with muscle degeneration. We also analysed collagen turnover pathways underlying fibrosis development in cultured primary quadriceps-derived fibroblasts. Collagen secretion and matrix metalloproteinases (MMPs) remained unaffected in both young and adult mdx compared to wt fibroblasts, whereas collagen cross-linking and tissue inhibitors of MMP (TIMP) expression significantly increased. We conclude that, in the DMD model we used, fibrosis mostly affects diaphragm and quadriceps with a higher collagen cross-linking and inhibition of MMPs that contribute differently to progressive collagen accumulation during fibrotic remodelling. This study offers a comprehensive histological and molecular characterisation of DMD-associated muscle fibrosis; it may thus provide new targets for tailored therapeutic interventions. Full article
(This article belongs to the Special Issue Highlights in Pathophysiology of the Musculoskeletal System)
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14 pages, 2917 KiB  
Article
Muscle Fiber Composition Changes after Selective Nerve Innervation
by Shiho Watanabe, Hiroko Ochiai, Hisashi Sakuma, Taisuke Mori, Masaki Yazawa, Aiko Oka and Kazuo Kishi
Int. J. Mol. Sci. 2022, 23(14), 7856; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147856 - 16 Jul 2022
Cited by 1 | Viewed by 1592
Abstract
Facial nerve paralysis interferes with mimetic muscle function. To reconstruct natural facial movement, free muscle flaps are transplanted as new muscles. However, it is difficult to maintain resting tonus. A dual innervation technique in which other nerves such as the hypoglossal nerve or [...] Read more.
Facial nerve paralysis interferes with mimetic muscle function. To reconstruct natural facial movement, free muscle flaps are transplanted as new muscles. However, it is difficult to maintain resting tonus. A dual innervation technique in which other nerves such as the hypoglossal nerve or contralateral facial nerve are added is often applied. Using 10-week-old rats (n = 10), the masseteric and hypoglossal nerves were cut, and the distal stump of the masseteric nerve and the proximal stump of the hypoglossal nerve were then sutured (suture group). In the other group, the masseteric nerve was cut and cauterized (cut group). Immunohistochemistry and microarray were performed on the extracted masseter muscle. The immunohistochemistry results suggested that the muscles in the suture group obtained oxidative characteristics. The microarray showed the genes involved in mitochondrial function, including Perm1. In summary, our data support the validity of the dualinnervation technique for facial paralysis treatment. Full article
(This article belongs to the Special Issue Highlights in Pathophysiology of the Musculoskeletal System)
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24 pages, 4117 KiB  
Article
Lorentzian-Corrected Apparent Exchange-Dependent Relaxation (LAREX) Ω-Plot Analysis—An Adaptation for qCEST in a Multi-Pool System: Comprehensive In Silico, In Situ, and In Vivo Studies
by Karl Ludger Radke, Lena Marie Wilms, Miriam Frenken, Julia Stabinska, Marek Knet, Benedikt Kamp, Thomas Andreas Thiel, Timm Joachim Filler, Sven Nebelung, Gerald Antoch, Daniel Benjamin Abrar, Hans-Jörg Wittsack and Anja Müller-Lutz
Int. J. Mol. Sci. 2022, 23(13), 6920; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23136920 - 22 Jun 2022
Cited by 7 | Viewed by 2178
Abstract
Based on in silico, in situ, and in vivo studies, this study aims to develop a new method for the quantitative chemical exchange saturation transfer (qCEST) technique considering multi-pool systems. To this end, we extended the state-of-the-art apparent exchange-dependent relaxation (AREX) method with [...] Read more.
Based on in silico, in situ, and in vivo studies, this study aims to develop a new method for the quantitative chemical exchange saturation transfer (qCEST) technique considering multi-pool systems. To this end, we extended the state-of-the-art apparent exchange-dependent relaxation (AREX) method with a Lorentzian correction (LAREX). We then validated this new method with in situ and in vivo experiments on human intervertebral discs (IVDs) using the Kendall-Tau correlation coefficient. In the in silico experiments, we observed significant deviations of the AREX method as a function of the underlying exchange rate (kba) and fractional concentration (fb) compared to the ground truth due to the influence of other exchange pools. In comparison to AREX, the LAREX-based Ω-plot approach yielded a substantial improvement. In the subsequent in situ and in vivo experiments on human IVDs, no correlation to the histological reference standard or Pfirrmann classification could be found for the fb (in situ: τ = −0.17 p = 0.51; in vivo: τ = 0.13 p = 0.30) and kba (in situ: τ = 0.042 p = 0.87; in vivo: τ = −0.26 p = 0.04) of Glycosaminoglycan (GAG) with AREX. In contrast, the influence of interfering pools could be corrected by LAREX, and a moderate to strong correlation was observed for the fractional concentration of GAG for both in situ (τ = −0.71 p = 0.005) and in vivo (τ = −0.49 p < 0.001) experiments. The study presented here is the first to introduce a new qCEST method that enables qCEST imaging in systems with multiple proton pools. Full article
(This article belongs to the Special Issue Highlights in Pathophysiology of the Musculoskeletal System)
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16 pages, 2460 KiB  
Article
Beneficial Effect of H2S-Releasing Molecules in an In Vitro Model of Sarcopenia: Relevance of Glucoraphanin
by Laura Micheli, Emma Mitidieri, Carlotta Turnaturi, Domenico Vanacore, Clara Ciampi, Elena Lucarini, Giuseppe Cirino, Carla Ghelardini, Raffaella Sorrentino, Lorenzo Di Cesare Mannelli and Roberta d’Emmanuele di Villa Bianca
Int. J. Mol. Sci. 2022, 23(11), 5955; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23115955 - 25 May 2022
Cited by 6 | Viewed by 2209
Abstract
Sarcopenia is a gradual and generalized skeletal muscle (SKM) syndrome, characterized by the impairment of muscle components and functionality. Hydrogen sulfide (H2S), endogenously formed within the body from the activity of cystathionine-γ-lyase (CSE), cystathionine- β-synthase (CBS), and mercaptopyruvate sulfurtransferase, is involved [...] Read more.
Sarcopenia is a gradual and generalized skeletal muscle (SKM) syndrome, characterized by the impairment of muscle components and functionality. Hydrogen sulfide (H2S), endogenously formed within the body from the activity of cystathionine-γ-lyase (CSE), cystathionine- β-synthase (CBS), and mercaptopyruvate sulfurtransferase, is involved in SKM function. Here, in an in vitro model of sarcopenia based on damage induced by dexamethasone (DEX, 1 μM, 48 h treatment) in C2C12-derived myotubes, we investigated the protective potential of exogenous and endogenous sources of H2S, i.e., glucoraphanin (30 μM), L-cysteine (150 μM), and 3-mercaptopyruvate (150 μM). DEX impaired the H2S signalling in terms of a reduction in CBS and CSE expression and H2S biosynthesis. Glucoraphanin and 3-mercaptopyruvate but not L-cysteine prevented the apoptotic process induced by DEX. In parallel, the H2S-releasing molecules reduced the oxidative unbalance evoked by DEX, reducing catalase activity, O2− levels, and protein carbonylation. Glucoraphanin, 3-mercaptopyruvate, and L-cysteine avoided the changes in myotubes morphology and morphometrics after DEX treatment. In conclusion, in an in vitro model of sarcopenia, an impairment in CBS/CSE/H2S signalling occurs, whereas glucoraphanin, a natural H2S-releasing molecule, appears more effective for preventing the SKM damage. Therefore, glucoraphanin supplementation could be an innovative therapeutic approach in the management of sarcopenia. Full article
(This article belongs to the Special Issue Highlights in Pathophysiology of the Musculoskeletal System)
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16 pages, 2463 KiB  
Article
The Role of IgG Fc Region N-Glycosylation in the Pathomechanism of Rheumatoid Arthritis
by Balázs Gyebrovszki, András Ács, Dániel Szabó, Felícia Auer, Soma Novozánszki, Bernadette Rojkovich, Anna Magyar, Ferenc Hudecz, Károly Vékey, László Drahos and Gabriella Sármay
Int. J. Mol. Sci. 2022, 23(10), 5828; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105828 - 23 May 2022
Cited by 6 | Viewed by 2282
Abstract
Anti-citrullinated protein antibodies (ACPAs) are involved in the pathogenesis of rheumatoid arthritis. N-glycosylation pattern of ACPA-IgG and healthy IgG Fc differs. The aim of this study is to determine the relative sialylation and galactosylation level of ACPAs and control IgG to assess their [...] Read more.
Anti-citrullinated protein antibodies (ACPAs) are involved in the pathogenesis of rheumatoid arthritis. N-glycosylation pattern of ACPA-IgG and healthy IgG Fc differs. The aim of this study is to determine the relative sialylation and galactosylation level of ACPAs and control IgG to assess their capability of inducing TNFα production, and furthermore, to analyze the correlations between the composition of Fc glycans and inflammatory markers in RA. We isolated IgG from sera of healthy volunteers and RA patients, and purified ACPAs on a citrulline-peptide column. Immunocomplexes (IC) were formed by adding an F(ab)2 fragment of anti-human IgG. U937 cells were used to monitor the binding of IC to FcγR and to trigger TNFα release determined by ELISA. To analyze glycan profiles, control IgG and ACPA-IgG were digested with trypsin and the glycosylation patterns of glycopeptides were analyzed by determining site-specific N-glycosylation using nano-UHPLC-MS/MS. We found that both sialylation and galactosylation levels of ACPA-IgG negatively correlate with inflammation-related parameters such as CRP, ESR, and RF. Functional assays show that dimerized ACPA-IgG significantly enhances TNFα release in an FcγRI-dependent manner, whereas healthy IgG does not. TNFα production inversely correlates with the relative intensities of the G0 glycoform, which lacks galactose and terminal sialic acid moieties. Full article
(This article belongs to the Special Issue Highlights in Pathophysiology of the Musculoskeletal System)
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19 pages, 2956 KiB  
Article
Characterization of the Skeletal Muscle Proteome in Undernourished Old Rats
by Caroline Barbé, Jérôme Salles, Christophe Chambon, Christophe Giraudet, Phelipe Sanchez, Véronique Patrac, Philippe Denis, Yves Boirie, Stéphane Walrand and Marine Gueugneau
Int. J. Mol. Sci. 2022, 23(9), 4762; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094762 - 26 Apr 2022
Cited by 4 | Viewed by 1950
Abstract
Aging is associated with a progressive loss of skeletal muscle mass and function termed sarcopenia. Various metabolic alterations that occur with aging also increase the risk of undernutrition, which can worsen age-related sarcopenia. However, the impact of undernutrition on aged skeletal muscle remains [...] Read more.
Aging is associated with a progressive loss of skeletal muscle mass and function termed sarcopenia. Various metabolic alterations that occur with aging also increase the risk of undernutrition, which can worsen age-related sarcopenia. However, the impact of undernutrition on aged skeletal muscle remains largely under-researched. To build a deeper understanding of the cellular and molecular mechanisms underlying age-related sarcopenia, we characterized the undernutrition-induced changes in the skeletal muscle proteome in old rats. For this study, 20-month-old male rats were fed 50% or 100% of their spontaneous intake for 12 weeks, and proteomic analysis was performed on both slow- and fast-twitch muscles. Proteomic profiling of undernourished aged skeletal muscle revealed that undernutrition has profound effects on muscle proteome independently of its effect on muscle mass. Undernutrition-induced changes in muscle proteome appear to be muscle-type-specific: slow-twitch muscle showed a broad pattern of differential expression in proteins important for energy metabolism, whereas fast-twitch muscle mainly showed changes in protein turnover between undernourished and control rats. This first proteomic analysis of undernourished aged skeletal muscle provides new molecular-level insight to explain phenotypic changes in undernourished aged muscle. We anticipate this work as a starting point to define new biomarkers associated with undernutrition-induced muscle loss in the elderly. Full article
(This article belongs to the Special Issue Highlights in Pathophysiology of the Musculoskeletal System)
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15 pages, 5324 KiB  
Article
Description of Osmolyte Pathways in Maturing Mdx Mice Reveals Altered Levels of Taurine and Sodium/Myo-Inositol Co-Transporters
by Caroline Merckx, Gwenny Cosemans, Jana Zschüntzsch, Robrecht Raedt, Jens Schmidt, Boel De Paepe and Jan L. De Bleecker
Int. J. Mol. Sci. 2022, 23(6), 3251; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063251 - 17 Mar 2022
Cited by 2 | Viewed by 1744
Abstract
Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration. Osmotic stress participates to DMD pathology and altered levels of osmolyte pathway members have been reported. The goal of this study was to gain insight in osmoregulatory changes in the [...] Read more.
Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration. Osmotic stress participates to DMD pathology and altered levels of osmolyte pathway members have been reported. The goal of this study was to gain insight in osmoregulatory changes in the mdx mouse model by examining the expression of osmolyte pathway members, including taurine transporter (TauT), sodium myo-inositol co-transporter (SMIT), betaine GABA transporter (BGT), and aldose reductase (AR) in the skeletal muscles and diaphragm of mdx mice aged 4, 8, 12, and 26 weeks. Necrosis was most prominent in 12 week-old mdx mice, whereas the amount of regenerated fibers increased until week 26 in the tibialis anterior. TauT protein levels were downregulated in the tibialis anterior and gastrocnemius of 4 to 12 week-old mdx mice, but not in 26 week-old mice, whereas TauT levels in the diaphragm remained significantly lower in 26 week-old mdx mice. In contrast, SMIT protein levels were significantly higher in the muscles of mdx mice when compared to controls. Our study revealed differential regulation of osmolyte pathway members in mdx muscle, which points to their complex involvement in DMD pathogenesis going beyond general osmotic stress responses. These results highlight the potential of osmolyte pathway members as a research interest and future therapeutic target in dystrophinopathy. Full article
(This article belongs to the Special Issue Highlights in Pathophysiology of the Musculoskeletal System)
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15 pages, 3005 KiB  
Article
Statins Aggravate the Risk of Insulin Resistance in Human Muscle
by Stefanie A. Grunwald, Stefanie Haafke, Ulrike Grieben, Ursula Kassner, Elisabeth Steinhagen-Thiessen and Simone Spuler
Int. J. Mol. Sci. 2022, 23(4), 2398; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042398 - 21 Feb 2022
Cited by 11 | Viewed by 4341
Abstract
Beside their beneficial effects on cardiovascular events, statins are thought to contribute to insulin resistance and type-2 diabetes. It is not known whether these effects are long-term events from statin-treatment or already triggered with the first statin-intake. Skeletal muscle is considered the main [...] Read more.
Beside their beneficial effects on cardiovascular events, statins are thought to contribute to insulin resistance and type-2 diabetes. It is not known whether these effects are long-term events from statin-treatment or already triggered with the first statin-intake. Skeletal muscle is considered the main site for insulin-stimulated glucose uptake and therefore, a primary target for insulin resistance in the human body. We analyzed localization and expression of proteins related to GLUT4 mediated glucose uptake via AMPKα or AKT in human skeletal muscle tissue from patients with statin-intake >6 months and in primary human myotubes after 96 h statin treatment. The ratio for AMPKα activity significantly increased in human skeletal muscle cells treated with statins for long- and short-term. Furthermore, the insulin-stimulated counterpart, AKT, significantly decreased in activity and protein level, while GSK3ß and mTOR protein expression reduced in statin-treated primary human myotubes, only. However, GLUT4 was normally distributed whereas CAV3 was internalized from plasma membrane around the nucleus in statin-treated primary human myotubes. Statin-treatment activates AMPKα-dependent glucose uptake and remains active after long-term statin treatment. Permanent blocking of its insulin-dependent counterpart AKT activation may lead to metabolic inflexibility and insulin resistance in the long run and may be a direct consequence of statin-treatment. Full article
(This article belongs to the Special Issue Highlights in Pathophysiology of the Musculoskeletal System)
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Review

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14 pages, 1156 KiB  
Review
Role of Sirtuins in the Pathogenesis of Rheumatoid Arthritis
by Agata Poniewierska-Baran, Oliwia Bochniak, Paulina Warias and Andrzej Pawlik
Int. J. Mol. Sci. 2023, 24(2), 1532; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24021532 - 12 Jan 2023
Cited by 5 | Viewed by 2145
Abstract
Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease leading to joint destruction. The causes of RA are not fully known. Most likely, the development of the disease depends on the coexistence of many factors, such as hereditary factors, immune system defects, gender, [...] Read more.
Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease leading to joint destruction. The causes of RA are not fully known. Most likely, the development of the disease depends on the coexistence of many factors, such as hereditary factors, immune system defects, gender, infectious agents, nicotine, and stress. Various epigenetic changes have been identified and correlated with the aggressive phenotype of RA, including the involvement of sirtuins, which are enzymes found in all living organisms. Their high content in the human body can slow down the aging processes, reduce cell death, counteract the appearance of inflammation, and regulate metabolic processes. Sirtuins can participate in several steps of RA pathogenesis. This narrative review presents, collects, and discusses the role of all sirtuins (1–7) in the pathogenesis of rheumatoid arthritis. Full article
(This article belongs to the Special Issue Highlights in Pathophysiology of the Musculoskeletal System)
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23 pages, 1617 KiB  
Review
Multipotential Role of Growth Factor Mimetic Peptides for Osteochondral Tissue Engineering
by Maria Giovanna Rizzo, Nicoletta Palermo, Ugo D’Amora, Salvatore Oddo, Salvatore Pietro Paolo Guglielmino, Sabrina Conoci, Marta Anna Szychlinska and Giovanna Calabrese
Int. J. Mol. Sci. 2022, 23(13), 7388; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137388 - 02 Jul 2022
Cited by 9 | Viewed by 4207
Abstract
Articular cartilage is characterized by a poor self-healing capacity due to its aneural and avascular nature. Once injured, it undergoes a series of catabolic processes which lead to its progressive degeneration and the onset of a severe chronic disease called osteoarthritis (OA). In [...] Read more.
Articular cartilage is characterized by a poor self-healing capacity due to its aneural and avascular nature. Once injured, it undergoes a series of catabolic processes which lead to its progressive degeneration and the onset of a severe chronic disease called osteoarthritis (OA). In OA, important alterations of the morpho-functional organization occur in the cartilage extracellular matrix, involving all the nearby tissues, including the subchondral bone. Osteochondral engineering, based on a perfect combination of cells, biomaterials and biomolecules, is becoming increasingly successful for the regeneration of injured cartilage and underlying subchondral bone tissue. To this end, recently, several peptides have been explored as active molecules and enrichment motifs for the functionalization of biomaterials due to their ability to be easily chemically synthesized, as well as their tunable physico-chemical features, low immunogenicity issues and functional group modeling properties. In addition, they have shown a good aptitude to penetrate into the tissue due to their small size and stability at room temperature. In particular, growth-factor-derived peptides can play multiple functions in bone and cartilage repair, exhibiting chondrogenic/osteogenic differentiation properties. Among the most studied peptides, great attention has been paid to transforming growth factor-β and bone morphogenetic protein mimetic peptides, cell-penetrating peptides, cell-binding peptides, self-assembling peptides and extracellular matrix-derived peptides. Moreover, recently, phage display technology is emerging as a powerful selection technique for obtaining functional peptides on a large scale and at a low cost. In particular, these peptides have demonstrated advantages such as high biocompatibility; the ability to be immobilized directly on chondro- and osteoinductive nanomaterials; and improving the cell attachment, differentiation, development and regeneration of osteochondral tissue. In this context, the aim of the present review was to go through the recent literature underlining the importance of studying novel functional motifs related to growth factor mimetic peptides that could be a useful tool in osteochondral repair strategies. Moreover, the review summarizes the current knowledge of the use of phage display peptides in osteochondral tissue regeneration. Full article
(This article belongs to the Special Issue Highlights in Pathophysiology of the Musculoskeletal System)
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16 pages, 1136 KiB  
Review
Muscle Wasting in Chronic Kidney Disease: Mechanism and Clinical Implications—A Narrative Review
by Tsai-Chin Cheng, Shou-Hsien Huang, Chung-Lan Kao and Po-Cheng Hsu
Int. J. Mol. Sci. 2022, 23(11), 6047; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23116047 - 27 May 2022
Cited by 17 | Viewed by 5218
Abstract
Muscle wasting, known to develop in patients with chronic kidney disease (CKD), is a deleterious consequence of numerous complications associated with deteriorated renal function. Muscle wasting in CKD mainly involves dysregulated muscle protein metabolism and impaired muscle cell regeneration. In this narrative review, [...] Read more.
Muscle wasting, known to develop in patients with chronic kidney disease (CKD), is a deleterious consequence of numerous complications associated with deteriorated renal function. Muscle wasting in CKD mainly involves dysregulated muscle protein metabolism and impaired muscle cell regeneration. In this narrative review, we discuss the cardinal role of the insulin-like growth factor 1 and myostatin signaling pathways, which have been extensively investigated using animal and human studies, as well as the emerging concepts in microRNA- and gut microbiota-mediated regulation of muscle mass and myogenesis. To ameliorate muscle loss, therapeutic strategies, including nutritional support, exercise programs, pharmacological interventions, and physical modalities, are being increasingly developed based on advances in understanding its underlying pathophysiology. Full article
(This article belongs to the Special Issue Highlights in Pathophysiology of the Musculoskeletal System)
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14 pages, 2088 KiB  
Review
Cancer-Related Cachexia: The Vicious Circle between Inflammatory Cytokines, Skeletal Muscle, Lipid Metabolism and the Possible Role of Physical Training
by Giuseppe Donato Mangano, Malak Fouani, Daniela D’Amico, Valentina Di Felice and Rosario Barone
Int. J. Mol. Sci. 2022, 23(6), 3004; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063004 - 10 Mar 2022
Cited by 13 | Viewed by 3296
Abstract
Cachexia is a multifactorial and multi-organ syndrome that is a major cause of morbidity and mortality in late-stage chronic diseases. The main clinical features of cancer-related cachexia are chronic inflammation, wasting of skeletal muscle and adipose tissue, insulin resistance, anorexia, and impaired myogenesis. [...] Read more.
Cachexia is a multifactorial and multi-organ syndrome that is a major cause of morbidity and mortality in late-stage chronic diseases. The main clinical features of cancer-related cachexia are chronic inflammation, wasting of skeletal muscle and adipose tissue, insulin resistance, anorexia, and impaired myogenesis. A multimodal treatment has been suggested to approach the multifactorial genesis of cachexia. In this context, physical exercise has been found to have a general effect on maintaining homeostasis in a healthy life, involving multiple organs and their metabolism. The purpose of this review is to present the evidence for the relationship between inflammatory cytokines, skeletal muscle, and fat metabolism and the potential role of exercise training in breaking the vicious circle of this impaired tissue cross-talk. Due to the wide-ranging effects of exercise training, from the body to the behavior and cognition of the individual, it seems to be able to improve the quality of life in this syndrome. Therefore, studying the molecular effects of physical exercise could provide important information about the interactions between organs and the systemic mediators involved in the overall homeostasis of the body. Full article
(This article belongs to the Special Issue Highlights in Pathophysiology of the Musculoskeletal System)
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18 pages, 1290 KiB  
Review
Leptin in Osteoarthritis and Rheumatoid Arthritis: Player or Bystander?
by Djedjiga Ait Eldjoudi, Alfonso Cordero Barreal, María Gonzalez-Rodríguez, Clara Ruiz-Fernández, Yousof Farrag, Mariam Farrag, Francisca Lago, Maurizio Capuozzo, Miguel Angel Gonzalez-Gay, Antonio Mera Varela, Jesús Pino and Oreste Gualillo
Int. J. Mol. Sci. 2022, 23(5), 2859; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052859 - 05 Mar 2022
Cited by 21 | Viewed by 4021
Abstract
White adipose tissue (WAT) is a specialized tissue whose main function is lipid synthesis and triglyceride storage. It is now considered as an active organ secreting a plethora of hormones and cytokines namely adipokines. Discovered in 1994, leptin has emerged as a key [...] Read more.
White adipose tissue (WAT) is a specialized tissue whose main function is lipid synthesis and triglyceride storage. It is now considered as an active organ secreting a plethora of hormones and cytokines namely adipokines. Discovered in 1994, leptin has emerged as a key molecule with pleiotropic functions. It is primarily recognized for its role in regulating energy homeostasis and food intake. Currently, further evidence suggests its potent role in reproduction, glucose metabolism, hematopoiesis, and interaction with the immune system. It is implicated in both innate and adaptive immunity, and it is reported to contribute, with other adipokines, in the cross-talking networks involved in the pathogenesis of chronic inflammation and immune-related diseases of the musculo-skeletal system such as osteoarthritis (OA) and rheumatoid arthritis (RA). In this review, we summarize the most recent findings concerning the involvement of leptin in immunity and inflammatory responses in OA and RA. Full article
(This article belongs to the Special Issue Highlights in Pathophysiology of the Musculoskeletal System)
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