International Journal of Molecular Sciences

Editorial

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3 pages, 185 KiB

Open AccessEditorial

Muscle Research: A Tour d’Horizon

by Carlo Zancanaro

Int. J. Mol. Sci. 2022, 23(3), 1585; https://doi.org/10.3390/ijms23031585 - 29 Jan 2022

Viewed by 1525

Abstract

The Special Issue on the “Muscular Structure, Physiology and Metabolism” was proposed in order to maintain the referenced scientific community abreast with recent research advancements regarding the morphology, functionality, and metabolism of muscle tissue, including a total of eighteen published papers, of which [...] Read more.

The Special Issue on the “Muscular Structure, Physiology and Metabolism” was proposed in order to maintain the referenced scientific community abreast with recent research advancements regarding the morphology, functionality, and metabolism of muscle tissue, including a total of eighteen published papers, of which twelve were original research manuscripts and six were review papers [...] Full article

(This article belongs to the Special Issue Muscular Structure, Physiology and Metabolism)

Research

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16 pages, 1621 KiB

Open AccessArticle

Comprehensive Simulation of Ca²⁺ Transients in the Continuum of Mouse Skeletal Muscle Fiber Types

by Oscar A. Rincón, Andrés F. Milán, Juan C. Calderón and Marco A. Giraldo

Int. J. Mol. Sci. 2021, 22(22), 12378; https://doi.org/10.3390/ijms222212378 - 17 Nov 2021

Cited by 4 | Viewed by 3034

Abstract

Mag-Fluo-4 has revealed differences in the kinetics of the Ca²⁺ transients of mammalian fiber types (I, IIA, IIX, and IIB). We simulated the changes in [Ca²⁺] through the sarcomere of these four fiber types, considering classical (troponin –Tn–, parvalbumin –Pv–, [...] Read more.

Mag-Fluo-4 has revealed differences in the kinetics of the Ca²⁺ transients of mammalian fiber types (I, IIA, IIX, and IIB). We simulated the changes in [Ca²⁺] through the sarcomere of these four fiber types, considering classical (troponin –Tn–, parvalbumin –Pv–, adenosine triphosphate –ATP–, sarcoplasmic reticulum Ca²⁺ pump –SERCA–, and dye) and new (mitochondria –MITO–, Na⁺/Ca²⁺ exchanger –NCX–, and store-operated calcium entry –SOCE–) Ca²⁺ binding sites, during single and tetanic stimulation. We found that during a single twitch, the sarcoplasmic peak [Ca²⁺] for fibers type IIB and IIX was around 16 µM, and for fibers type I and IIA reached 10–13 µM. The release rate in fibers type I, IIA, IIX, and IIB was 64.8, 153.6, 238.8, and 244.5 µM ms⁻¹, respectively. Both the pattern of change and the peak concentrations of the Ca²⁺-bound species in the sarcoplasm (Tn, PV, ATP, and dye), the sarcolemma (NCX, SOCE), and the SR (SERCA) showed the order IIB ≥ IIX > IIA > I. The capacity of the NCX was 2.5, 1.3, 0.9, and 0.8% of the capacity of SERCA, for fibers type I, IIA, IIX, and IIB, respectively. MITO peak [Ca²⁺] ranged from 0.93 to 0.23 µM, in fibers type I and IIB, respectively, while intermediate values were obtained in fibers IIA and IIX. The latter numbers doubled during tetanic stimulation. In conclusion, we presented a comprehensive mathematical model of the excitation–contraction coupling that integrated most classical and novel Ca²⁺ handling mechanisms, overcoming the limitations of the fast- vs. slow-fibers dichotomy and the use of slow dyes. Full article

(This article belongs to the Special Issue Muscular Structure, Physiology and Metabolism)

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20 pages, 5822 KiB

Open AccessArticle

Genetically Encoded Biosensors to Monitor Intracellular Reactive Oxygen and Nitrogen Species and Glutathione Redox Potential in Skeletal Muscle Cells

by Escarlata Fernández-Puente and Jesús Palomero

Int. J. Mol. Sci. 2021, 22(19), 10876; https://doi.org/10.3390/ijms221910876 - 8 Oct 2021

Cited by 8 | Viewed by 2797

Abstract

Reactive oxygen and nitrogen species (RONS) play an important role in the pathophysiology of skeletal muscle and are involved in the regulation of intracellular signaling pathways, which drive metabolism, regeneration, and adaptation in skeletal muscle. However, the molecular mechanisms underlying these processes are [...] Read more.

Reactive oxygen and nitrogen species (RONS) play an important role in the pathophysiology of skeletal muscle and are involved in the regulation of intracellular signaling pathways, which drive metabolism, regeneration, and adaptation in skeletal muscle. However, the molecular mechanisms underlying these processes are unknown or partially uncovered. We implemented a combination of methodological approaches that are funded for the use of genetically encoded biosensors associated with quantitative fluorescence microscopy imaging to study redox biology in skeletal muscle. Therefore, it was possible to detect and monitor RONS and glutathione redox potential with high specificity and spatio-temporal resolution in two models, isolated skeletal muscle fibers and C2C12 myoblasts/myotubes. Biosensors HyPer3 and roGFP2-Orp1 were examined for the detection of cytosolic hydrogen peroxide; HyPer-mito and HyPer-nuc for the detection of mitochondrial and nuclear hydrogen peroxide; Mito-Grx1-roGFP2 and cyto-Grx1-roGFP2 were used for registration of the glutathione redox potential in mitochondria and cytosol. G-geNOp was proven to detect cytosolic nitric oxide. The fluorescence emitted by the biosensors is affected by pH, and this might have masked the results; therefore, environmental CO₂ must be controlled to avoid pH fluctuations. In conclusion, genetically encoded biosensors and quantitative fluorescence microscopy provide a robust methodology to investigate the pathophysiological processes associated with the redox biology of skeletal muscle. Full article

(This article belongs to the Special Issue Muscular Structure, Physiology and Metabolism)

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21 pages, 3769 KiB

Open AccessArticle

Age-Related Changes in the Matrisome of the Mouse Skeletal Muscle

by Francesco Demetrio Lofaro, Barbara Cisterna, Maria Assunta Lacavalla, Federico Boschi, Manuela Malatesta, Daniela Quaglino, Carlo Zancanaro and Federica Boraldi

Int. J. Mol. Sci. 2021, 22(19), 10564; https://doi.org/10.3390/ijms221910564 - 29 Sep 2021

Cited by 24 | Viewed by 3351

Abstract

Aging is characterized by a progressive decline of skeletal muscle (SM) mass and strength which may lead to sarcopenia in older persons. To date, a limited number of studies have been performed in the old SM looking at the whole, complex network of [...] Read more.

Aging is characterized by a progressive decline of skeletal muscle (SM) mass and strength which may lead to sarcopenia in older persons. To date, a limited number of studies have been performed in the old SM looking at the whole, complex network of the extracellular matrix (i.e., matrisome) and its aging-associated changes. In this study, skeletal muscle proteins were isolated from whole gastrocnemius muscles of adult (12 mo.) and old (24 mo.) mice using three sequential extractions, each one analyzed by liquid chromatography with tandem mass spectrometry. Muscle sections were investigated using fluorescence- and transmission electron microscopy. This study provided the first characterization of the matrisome in the old SM demonstrating several statistically significantly increased matrisome proteins in the old vs. adult SM. Several proteomic findings were confirmed and expanded by morphological data. The current findings shed new light on the mutually cooperative interplay between cells and the extracellular environment in the aging SM. These data open the door for a better understanding of the mechanisms modulating myocellular behavior in aging (e.g., by altering mechano-sensing stimuli as well as signaling pathways) and their contribution to age-dependent muscle dysfunction. Full article

(This article belongs to the Special Issue Muscular Structure, Physiology and Metabolism)

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30 pages, 7059 KiB

Open AccessArticle

A Modular Mathematical Model of Exercise-Induced Changes in Metabolism, Signaling, and Gene Expression in Human Skeletal Muscle

by Ilya R. Akberdin, Ilya N. Kiselev, Sergey S. Pintus, Ruslan N. Sharipov, Alexander Yu Vertyshev, Olga L. Vinogradova, Daniil V. Popov and Fedor A. Kolpakov

Int. J. Mol. Sci. 2021, 22(19), 10353; https://doi.org/10.3390/ijms221910353 - 26 Sep 2021

Cited by 11 | Viewed by 4470

Abstract

Skeletal muscle is the principal contributor to exercise-induced changes in human metabolism. Strikingly, although it has been demonstrated that a lot of metabolites accumulating in blood and human skeletal muscle during an exercise activate different signaling pathways and induce the expression of many [...] Read more.

Skeletal muscle is the principal contributor to exercise-induced changes in human metabolism. Strikingly, although it has been demonstrated that a lot of metabolites accumulating in blood and human skeletal muscle during an exercise activate different signaling pathways and induce the expression of many genes in working muscle fibres, the systematic understanding of signaling–metabolic pathway interrelations with downstream genetic regulation in the skeletal muscle is still elusive. Herein, a physiologically based computational model of skeletal muscle comprising energy metabolism, Ca²⁺, and AMPK (AMP-dependent protein kinase) signaling pathways and the expression regulation of genes with early and delayed responses was developed based on a modular modeling approach and included 171 differential equations and more than 640 parameters. The integrated modular model validated on diverse including original experimental data and different exercise modes provides a comprehensive in silico platform in order to decipher and track cause–effect relationships between metabolic, signaling, and gene expression levels in skeletal muscle. Full article

(This article belongs to the Special Issue Muscular Structure, Physiology and Metabolism)

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20 pages, 56852 KiB

Open AccessArticle

Advanced Glycation End Products Are Retained in Decellularized Muscle Matrix Derived from Aged Skeletal Muscle

by Lucas C. Olson, Tri M. Nguyen, Rebecca L. Heise, Barbara D. Boyan, Zvi Schwartz and Michael J. McClure

Int. J. Mol. Sci. 2021, 22(16), 8832; https://doi.org/10.3390/ijms22168832 - 17 Aug 2021

Cited by 10 | Viewed by 4598

Abstract

Decellularized tissues are biocompatible materials that engraft well, but the age of their source has not been explored for clinical translation. Advanced glycation end products (AGEs) are chemical cross-links that accrue on skeletal muscle collagen in old age, stiffening the matrix and increasing [...] Read more.

Decellularized tissues are biocompatible materials that engraft well, but the age of their source has not been explored for clinical translation. Advanced glycation end products (AGEs) are chemical cross-links that accrue on skeletal muscle collagen in old age, stiffening the matrix and increasing inflammation. Whether decellularized biomaterials derived from aged muscle would suffer from increased AGE collagen cross-links is unknown. We characterized gastrocnemii of 1-, 2-, and 20-month-old C57BL/6J mice before and after decellularization to determine age-dependent changes to collagen stiffness and AGE cross-linking. Total and soluble collagen was measured to assess if age-dependent increases in collagen and cross-linking persisted in decellularized muscle matrix (DMM). Stiffness of aged DMM was determined using atomic force microscopy. AGE levels and the effect of an AGE cross-link breaker, ALT-711, were tested in DMM samples. Our results show that age-dependent increases in collagen amount, cross-linking, and general stiffness were observed in DMM. Notably, we measured increased AGE-specific cross-links within old muscle, and observed that old DMM retained AGE cross-links using ALT-711 to reduce AGE levels. In conclusion, deleterious age-dependent modifications to collagen are present in DMM from old muscle, implying that age matters when sourcing skeletal muscle extracellular matrix as a biomaterial. Full article

(This article belongs to the Special Issue Muscular Structure, Physiology and Metabolism)

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22 pages, 2166 KiB

Open AccessArticle

Study of the Expression and Function of Calcium-Sensing Receptor in Human Skeletal Muscle

by Cecilia Romagnoli, Preeti Sharma, Roberto Zonefrati, Gaia Palmini, Elena Lucattelli, Donald T. Ward, Isabella Ellinger, Marco Innocenti and Maria Luisa Brandi

Int. J. Mol. Sci. 2021, 22(14), 7282; https://doi.org/10.3390/ijms22147282 - 6 Jul 2021

Cited by 6 | Viewed by 3222

Abstract

Skeletal muscle has an outstanding capacity for regeneration in response to injuries, but there are disorders in which this process is seriously impaired, such as sarcopenia. Pharmacological treatments to restore muscle trophism are not available, therefore, the identification of suitable therapeutic targets that [...] Read more.

Skeletal muscle has an outstanding capacity for regeneration in response to injuries, but there are disorders in which this process is seriously impaired, such as sarcopenia. Pharmacological treatments to restore muscle trophism are not available, therefore, the identification of suitable therapeutic targets that could be useful for the treatment of skeletal reduced myogenesis is highly desirable. In this in vitro study, we explored the expression and function of the calcium-sensing receptor (CaSR) in human skeletal muscle tissues and their derived satellite cells. The results obtained from analyses with various techniques of gene and protein CaSR expression and of its secondary messengers in response to calcium (Ca²⁺) and CaSR drugs have demonstrated that this receptor is not present in human skeletal muscle tissues, neither in the established satellite cells, nor during in vitro myogenic differentiation. Taken together, our data suggest that, although CaSR is a very important drug target in physiology and pathology, this receptor probably does not have any physiological role in skeletal muscle in normal conditions. Full article

(This article belongs to the Special Issue Muscular Structure, Physiology and Metabolism)

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13 pages, 4300 KiB

Open AccessArticle

Ultrasonographic and Histological Correlation after Experimental Reconstruction of a Volumetric Muscle Loss Injury with Adipose Tissue

by Fernando Leiva-Cepas, Alberto Benito-Ysamat, Ignacio Jimena, Fernando Jimenez-Diaz, Maria Jesus Gil-Belmonte, Ignacio Ruz-Caracuel, Rafael Villalba and Jose Peña-Amaro

Int. J. Mol. Sci. 2021, 22(13), 6689; https://doi.org/10.3390/ijms22136689 - 22 Jun 2021

Cited by 5 | Viewed by 2420

Abstract

Different types of scaffolds are used to reconstruct muscle volume loss injuries. In this experimental study, we correlated ultrasound observations with histological findings in a muscle volume loss injury reconstructed with autologous adipose tissue. The outcome is compared with decellularized and porous matrix [...] Read more.

Different types of scaffolds are used to reconstruct muscle volume loss injuries. In this experimental study, we correlated ultrasound observations with histological findings in a muscle volume loss injury reconstructed with autologous adipose tissue. The outcome is compared with decellularized and porous matrix implants. Autologous adipose tissue, decellularized matrix, and a porous collagen matrix were implanted in volumetric muscle loss (VML) injuries generated on the anterior tibial muscles of Wistar rats. Sixty days after implantation, ultrasound findings were compared with histological and histomorphometric analysis. The muscles with an autologous adipose tissue implant exhibited an ultrasound pattern that was quite similar to that of the regenerative control muscles. From a histological point of view, the defects had been occupied by newly formed muscle tissue with certain structural abnormalities that would explain the differences between the ultrasound patterns of the normal control muscles and the regenerated ones. While the decellularized muscle matrix implant resulted in fibrosis and an inflammatory response, the porous collagen matrix implant was replaced by regenerative muscle fibers with neurogenic atrophy and fibrosis. In both cases, the ultrasound images reflected echogenic, echotextural, and vascular changes compatible with the histological findings of failed muscle regeneration. The ultrasound analysis confirmed the histological findings observed in the VML injuries reconstructed by autologous adipose tissue implantation. Ultrasound can be a useful tool for evaluating the structure of muscles reconstructed through tissue engineering. Full article

(This article belongs to the Special Issue Muscular Structure, Physiology and Metabolism)

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19 pages, 2711 KiB

Open AccessArticle

Ascorbic Acid Supplementation Improves Skeletal Muscle Growth in Pacu (Piaractus mesopotamicus) Juveniles: In Vivo and In Vitro Studies

by Bruna Tereza Thomazini Zanella, Isabele Cristina Magiore, Bruno Oliveira Silva Duran, Guilherme Gutierrez Pereira, Igor Simões Tiagua Vicente, Pedro Luiz Pucci Figueiredo Carvalho, Rondinelle Artur Simões Salomão, Edson Assunção Mareco, Robson Francisco Carvalho, Tassiana Gutierrez de Paula, Margarida Maria Barros and Maeli Dal-Pai-Silva

Int. J. Mol. Sci. 2021, 22(6), 2995; https://doi.org/10.3390/ijms22062995 - 15 Mar 2021

Cited by 11 | Viewed by 3096

Abstract

In fish, fasting leads to loss of muscle mass. This condition triggers oxidative stress, and therefore, antioxidants can be an alternative to muscle recovery. We investigated the effects of antioxidant ascorbic acid (AA) on the morphology, antioxidant enzyme activity, and gene expression in [...] Read more.

In fish, fasting leads to loss of muscle mass. This condition triggers oxidative stress, and therefore, antioxidants can be an alternative to muscle recovery. We investigated the effects of antioxidant ascorbic acid (AA) on the morphology, antioxidant enzyme activity, and gene expression in the skeletal muscle of pacu (Piaractus mesopotamicus) following fasting, using in vitro and in vivo strategies. Isolated muscle cells of the pacu were subjected to 72 h of nutrient restriction, followed by 24 h of incubation with nutrients or nutrients and AA (200 µM). Fish were fasted for 15 days, followed by 6 h and 15 and 30 days of refeeding with 100, 200, and 400 mg/kg of AA supplementation. AA addition increased cell diameter and the expression of anabolic and cell proliferation genes in vitro. In vivo, 400 mg/kg of AA increased anabolic and proliferative genes expression at 6 h of refeeding, the fiber diameter and the expression of genes related to cell proliferation at 15 days, and the expression of catabolic and oxidative metabolism genes at 30 days. Catalase activity remained low in the higher supplementation group. In conclusion, AA directly affected the isolated muscle cells, and the higher AA supplementation positively influenced muscle growth after fasting. Full article

(This article belongs to the Special Issue Muscular Structure, Physiology and Metabolism)

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15 pages, 2516 KiB

Open AccessArticle

Palmitic Acid Impairs Myogenesis and Alters Temporal Expression of miR-133a and miR-206 in C2C12 Myoblasts

by Ailma O. da Paixão, Anaysa Paola Bolin, João G. Silvestre and Alice Cristina Rodrigues

Int. J. Mol. Sci. 2021, 22(5), 2748; https://doi.org/10.3390/ijms22052748 - 9 Mar 2021

Cited by 13 | Viewed by 4040

Abstract

Palmitic acid (PA), a saturated fatty acid enriched in high-fat diet, has been implicated in the development of sarcopenic obesity. Herein, we chose two non-cytotoxic concentrations to better understand how excess PA could impact myotube formation or diameter without inducing cell death. Forty-eight [...] Read more.

Palmitic acid (PA), a saturated fatty acid enriched in high-fat diet, has been implicated in the development of sarcopenic obesity. Herein, we chose two non-cytotoxic concentrations to better understand how excess PA could impact myotube formation or diameter without inducing cell death. Forty-eight hours of 100 µM PA induced a reduction of myotube diameter and increased the number of type I fibers, which was associated with increased miR-206 expression. Next, C2C12 myotube growth in the presence of PA was evaluated. Compared to control cells, 150 µM PA reduces myoblast proliferation and the expression of MyoD and miR-206 and miR-133a expression, leading to a reduced number and diameter of myotubes. PA (100 µM), despite not affecting proliferation, impairs myotube formation by reducing the expression of Myf5 and miR-206 and decreasing protein synthesis. Interestingly, 100 and 150 µM PA-treated myotubes had a higher number of type II fibers than control cells. In conclusion, PA affects negatively myotube diameter, fusion, and metabolism, which may be related to myomiRs. By providing new insights into the mechanisms by which PA affects negatively skeletal muscle, our data may help in the discovery of new targets to treat sarcopenic obesity. Full article

(This article belongs to the Special Issue Muscular Structure, Physiology and Metabolism)

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14 pages, 1550 KiB

Open AccessArticle

Myocardial Hypertrophy and Compensatory Increase in Systolic Function in a Mouse Model of Oxidative Stress

by Rohan Varshney, Rojina Ranjit, Ying Ann Chiao, Michael Kinter and Bumsoo Ahn

Int. J. Mol. Sci. 2021, 22(4), 2039; https://doi.org/10.3390/ijms22042039 - 18 Feb 2021

Cited by 8 | Viewed by 3017

Abstract

Free radicals, or reactive oxygen species, have been implicated as one of the primary causes of myocardial pathologies elicited by chronic diseases and age. The imbalance between pro-oxidants and antioxidants, termed “oxidative stress”, involves several pathological changes in mouse hearts, including hypertrophy and [...] Read more.

Free radicals, or reactive oxygen species, have been implicated as one of the primary causes of myocardial pathologies elicited by chronic diseases and age. The imbalance between pro-oxidants and antioxidants, termed “oxidative stress”, involves several pathological changes in mouse hearts, including hypertrophy and cardiac dysfunction. However, the molecular mechanisms and adaptations of the hearts in mice lacking cytoplasmic superoxide dismutase (Sod1KO) have not been investigated. We used echocardiography to characterize cardiac function and morphology in vivo. Protein expression and enzyme activity of Sod1KO were confirmed by targeted mass spectrometry and activity gel. The heart weights of the Sod1KO mice were significantly increased compared with their wildtype peers. The increase in heart weights was accompanied by concentric hypertrophy, posterior wall thickness of the left ventricles (LV), and reduced LV volume. Activated downstream pathways in Sod1KO hearts included serine–threonine kinase and ribosomal protein synthesis. Notably, the reduction in LV volume was compensated by enhanced systolic function, measured by increased ejection fraction and fractional shortening. A regulatory sarcomeric protein, troponin I, was hyper-phosphorylated in Sod1KO, while the vinculin protein was upregulated. In summary, mice lacking cytoplasmic superoxide dismutase were associated with an increase in heart weights and concentric hypertrophy, exhibiting a pathological adaptation of the hearts to oxidative stress. Full article

(This article belongs to the Special Issue Muscular Structure, Physiology and Metabolism)

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20 pages, 2570 KiB

Open AccessArticle

Transcriptomic Signatures and Upstream Regulation in Human Skeletal Muscle Adapted to Disuse and Aerobic Exercise

by Pavel A. Makhnovskii, Roman O. Bokov, Fedor A. Kolpakov and Daniil V. Popov

Int. J. Mol. Sci. 2021, 22(3), 1208; https://doi.org/10.3390/ijms22031208 - 26 Jan 2021

Cited by 20 | Viewed by 3957

Abstract

Inactivity is associated with the development of numerous disorders. Regular aerobic exercise is broadly used as a key intervention to prevent and treat these pathological conditions. In our meta-analysis we aimed to identify and compare (i) the transcriptomic signatures related to disuse, regular [...] Read more.

Inactivity is associated with the development of numerous disorders. Regular aerobic exercise is broadly used as a key intervention to prevent and treat these pathological conditions. In our meta-analysis we aimed to identify and compare (i) the transcriptomic signatures related to disuse, regular and acute aerobic exercise in human skeletal muscle and (ii) the biological effects and transcription factors associated with these transcriptomic changes. A standardized workflow with robust cut-off criteria was used to analyze 27 transcriptomic datasets for the vastus lateralis muscle of healthy humans subjected to disuse, regular and acute aerobic exercise. We evaluated the role of transcriptional regulation in the phenotypic changes described in the literature. The responses to chronic interventions (disuse and regular training) partially correspond to the phenotypic effects. Acute exercise induces changes that are mainly related to the regulation of gene expression, including a strong enrichment of several transcription factors (most of which are related to the ATF/CREB/AP-1 superfamily) and a massive increase in the expression levels of genes encoding transcription factors and co-activators. Overall, the adaptation strategies of skeletal muscle to decreased and increased levels of physical activity differ in direction and demonstrate qualitative differences that are closely associated with the activation of different sets of transcription factors. Full article

(This article belongs to the Special Issue Muscular Structure, Physiology and Metabolism)

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13 pages, 4042 KiB

Open AccessArticle

Restoration of Sarcoplasmic Reticulum Ca²⁺ ATPase (SERCA) Activity Prevents Age-Related Muscle Atrophy and Weakness in Mice

by Rizwan Qaisar, Gavin Pharaoh, Shylesh Bhaskaran, Hongyang Xu, Rojina Ranjit, Jan Bian, Bumsoo Ahn, Constantin Georgescu, Jonathan D. Wren and Holly Van Remmen

Int. J. Mol. Sci. 2021, 22(1), 37; https://doi.org/10.3390/ijms22010037 - 22 Dec 2020

Cited by 30 | Viewed by 4581

Abstract

Sarcopenia has a significant negative impact on healthspan in the elderly and effective pharmacologic interventions remain elusive. We have previously demonstrated that sarcopenia is associated with reduced activity of the sarcoplasmic reticulum Ca²⁺ ATPase (SERCA) pump. We asked whether restoring SERCA activity [...] Read more.

Sarcopenia has a significant negative impact on healthspan in the elderly and effective pharmacologic interventions remain elusive. We have previously demonstrated that sarcopenia is associated with reduced activity of the sarcoplasmic reticulum Ca²⁺ ATPase (SERCA) pump. We asked whether restoring SERCA activity using pharmacologic activation in aging mice could mitigate the sarcopenia phenotype. We treated 16-month male C57BL/6J mice with vehicle or CDN1163, an allosteric SERCA activator, for 10 months. At 26 months, maximal SERCA activity was reduced 41% in gastrocnemius muscle in vehicle-treated mice but maintained in old CDN1163 treated mice. Reductions in gastrocnemius mass (9%) and in vitro specific force generation in extensor digitorum longus muscle (11%) in 26 versus 16-month-old wild-type mice were also reversed by CDN1163. CDN1163 administered by intra-peritoneal injection also prevented the increase in mitochondrial ROS production in gastrocnemius muscles of aged mice. Transcriptomic analysis revealed that these effects are at least in part mediated by enhanced cellular energetics by activation of PGC1-α, UCP1, HSF1, and APMK and increased regenerative capacity by suppression of MEF2C and p38 MAPK signaling. Together, these exciting findings are the first to support that pharmacological targeting of SERCA can be an effective therapy to counter age-related muscle dysfunction. Full article

(This article belongs to the Special Issue Muscular Structure, Physiology and Metabolism)

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Review

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14 pages, 1593 KiB

Open AccessReview

Ion Channels and Transporters in Muscle Cell Differentiation

by Lingye Chen, Fatemeh Hassani Nia and Tobias Stauber

Int. J. Mol. Sci. 2021, 22(24), 13615; https://doi.org/10.3390/ijms222413615 - 19 Dec 2021

Cited by 12 | Viewed by 4742

Abstract

Investigations on ion channels in muscle tissues have mainly focused on physiological muscle function and related disorders, but emerging evidence supports a critical role of ion channels and transporters in developmental processes, such as controlling the myogenic commitment of stem cells. In this [...] Read more.

Investigations on ion channels in muscle tissues have mainly focused on physiological muscle function and related disorders, but emerging evidence supports a critical role of ion channels and transporters in developmental processes, such as controlling the myogenic commitment of stem cells. In this review, we provide an overview of ion channels and transporters that influence skeletal muscle myoblast differentiation, cardiac differentiation from pluripotent stem cells, as well as vascular smooth muscle cell differentiation. We highlight examples of model organisms or patients with mutations in ion channels. Furthermore, a potential underlying molecular mechanism involving hyperpolarization of the resting membrane potential and a series of calcium signaling is discussed. Full article

(This article belongs to the Special Issue Muscular Structure, Physiology and Metabolism)

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17 pages, 1301 KiB

Open AccessReview

Available In Vitro Models for Human Satellite Cells from Skeletal Muscle

by Cecilia Romagnoli, Teresa Iantomasi and Maria Luisa Brandi

Int. J. Mol. Sci. 2021, 22(24), 13221; https://doi.org/10.3390/ijms222413221 - 8 Dec 2021

Cited by 21 | Viewed by 10047

Abstract

Skeletal muscle accounts for almost 40% of the total adult human body mass. This tissue is essential for structural and mechanical functions such as posture, locomotion, and breathing, and it is endowed with an extraordinary ability to adapt to physiological changes associated with [...] Read more.

Skeletal muscle accounts for almost 40% of the total adult human body mass. This tissue is essential for structural and mechanical functions such as posture, locomotion, and breathing, and it is endowed with an extraordinary ability to adapt to physiological changes associated with growth and physical exercise, as well as tissue damage. Moreover, skeletal muscle is the most age-sensitive tissue in mammals. Due to aging, but also to several diseases, muscle wasting occurs with a loss of muscle mass and functionality, resulting from disuse atrophy and defective muscle regeneration, associated with dysfunction of satellite cells, which are the cells responsible for maintaining and repairing adult muscle. The most established cell lines commonly used to study muscle homeostasis come from rodents, but there is a need to study skeletal muscle using human models, which, due to ethical implications, consist primarily of in vitro culture, which is the only alternative way to vertebrate model organisms. This review will survey in vitro 2D/3D models of human satellite cells to assess skeletal muscle biology for pre-clinical investigations and future directions. Full article

(This article belongs to the Special Issue Muscular Structure, Physiology and Metabolism)

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47 pages, 3643 KiB

Open AccessReview

Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances

by Raquel Gómez-Oca, Belinda S. Cowling and Jocelyn Laporte

Int. J. Mol. Sci. 2021, 22(21), 11377; https://doi.org/10.3390/ijms222111377 - 21 Oct 2021

Cited by 32 | Viewed by 6602

Abstract

Centronuclear myopathies (CNM) are rare congenital disorders characterized by muscle weakness and structural defects including fiber hypotrophy and organelle mispositioning. The main CNM forms are caused by mutations in: the MTM1 gene encoding the phosphoinositide phosphatase myotubularin (myotubular myopathy), the DNM2 gene encoding [...] Read more.

Centronuclear myopathies (CNM) are rare congenital disorders characterized by muscle weakness and structural defects including fiber hypotrophy and organelle mispositioning. The main CNM forms are caused by mutations in: the MTM1 gene encoding the phosphoinositide phosphatase myotubularin (myotubular myopathy), the DNM2 gene encoding the mechanoenzyme dynamin 2, the BIN1 gene encoding the membrane curvature sensing amphiphysin 2, and the RYR1 gene encoding the skeletal muscle calcium release channel/ryanodine receptor. MTM1, BIN1, and DNM2 proteins are involved in membrane remodeling and trafficking, while RyR1 directly regulates excitation-contraction coupling (ECC). Several CNM animal models have been generated or identified, which confirm shared pathological anomalies in T-tubule remodeling, ECC, organelle mispositioning, protein homeostasis, neuromuscular junction, and muscle regeneration. Dynamin 2 plays a crucial role in CNM physiopathology and has been validated as a common therapeutic target for three CNM forms. Indeed, the promising results in preclinical models set up the basis for ongoing clinical trials. Another two clinical trials to treat myotubular myopathy by MTM1 gene therapy or tamoxifen repurposing are also ongoing. Here, we review the contribution of the different CNM models to understanding physiopathology and therapy development with a focus on the commonly dysregulated pathways and current therapeutic targets. Full article

(This article belongs to the Special Issue Muscular Structure, Physiology and Metabolism)

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21 pages, 1802 KiB

Open AccessReview

The Role of GSK-3β in the Regulation of Protein Turnover, Myosin Phenotype, and Oxidative Capacity in Skeletal Muscle under Disuse Conditions

by Timur M. Mirzoev, Kristina A. Sharlo and Boris S. Shenkman

Int. J. Mol. Sci. 2021, 22(10), 5081; https://doi.org/10.3390/ijms22105081 - 11 May 2021

Cited by 36 | Viewed by 4963

Abstract

Skeletal muscles, being one of the most abundant tissues in the body, are involved in many vital processes, such as locomotion, posture maintenance, respiration, glucose homeostasis, etc. Hence, the maintenance of skeletal muscle mass is crucial for overall health, prevention of various diseases, [...] Read more.

Skeletal muscles, being one of the most abundant tissues in the body, are involved in many vital processes, such as locomotion, posture maintenance, respiration, glucose homeostasis, etc. Hence, the maintenance of skeletal muscle mass is crucial for overall health, prevention of various diseases, and contributes to an individual’s quality of life. Prolonged muscle inactivity/disuse (due to limb immobilization, mechanical ventilation, bedrest, spaceflight) represents one of the typical causes, leading to the loss of muscle mass and function. This disuse-induced muscle loss primarily results from repressed protein synthesis and increased proteolysis. Further, prolonged disuse results in slow-to-fast fiber-type transition, mitochondrial dysfunction and reduced oxidative capacity. Glycogen synthase kinase 3β (GSK-3β) is a key enzyme standing at the crossroads of various signaling pathways regulating a wide range of cellular processes. This review discusses various important roles of GSK-3β in the regulation of protein turnover, myosin phenotype, and oxidative capacity in skeletal muscles under disuse/unloading conditions and subsequent recovery. According to its vital functions, GSK-3β may represent a perspective therapeutic target in the treatment of muscle wasting induced by chronic disuse, aging, and a number of diseases. Full article

(This article belongs to the Special Issue Muscular Structure, Physiology and Metabolism)

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Open AccessReview

MiRNAs and Muscle Regeneration: Therapeutic Targets in Duchenne Muscular Dystrophy

by Amelia Eva Aránega, Estefanía Lozano-Velasco, Lara Rodriguez-Outeiriño, Felicitas Ramírez de Acuña, Diego Franco and Francisco Hernández-Torres

Int. J. Mol. Sci. 2021, 22(8), 4236; https://doi.org/10.3390/ijms22084236 - 19 Apr 2021

Cited by 18 | Viewed by 4708

Abstract

microRNAs (miRNAs) are small non-coding RNAs required for the post-transcriptional control of gene expression. MicroRNAs play a critical role in modulating muscle regeneration and stem cell behavior. Muscle regeneration is affected in muscular dystrophies, and a critical point for the development [...] Read more.

microRNAs (miRNAs) are small non-coding RNAs required for the post-transcriptional control of gene expression. MicroRNAs play a critical role in modulating muscle regeneration and stem cell behavior. Muscle regeneration is affected in muscular dystrophies, and a critical point for the development of effective strategies for treating muscle disorders is optimizing approaches to target muscle stem cells in order to increase the ability to regenerate lost tissue. Within this framework, miRNAs are emerging as implicated in muscle stem cell response in neuromuscular disorders and new methodologies to regulate the expression of key microRNAs are coming up. In this review, we summarize recent advances highlighting the potential of miRNAs to be used in conjunction with gene replacement therapies, in order to improve muscle regeneration in the context of Duchenne Muscular Dystrophy (DMD). Full article

(This article belongs to the Special Issue Muscular Structure, Physiology and Metabolism)

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