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Open AccessEditorial

Introduction to the Special Issue “Skeletal Muscle Atrophy: Mechanisms at a Cellular Level”

by Emanuela Zuccaro, Caterina Marchioretti, Marco Pirazzini and Maria Pennuto

Cells 2023, 12(3), 502; https://doi.org/10.3390/cells12030502 - 3 Feb 2023

Viewed by 4828

Abstract

Skeletal muscle is the most abundant tissue in the body and requires high levels of energy to function properly. Skeletal muscle allows voluntary movement and body posture, which require different types of fiber, innervation, energy, and metabolism. Here, we summarize the contribution received [...] Read more.

Skeletal muscle is the most abundant tissue in the body and requires high levels of energy to function properly. Skeletal muscle allows voluntary movement and body posture, which require different types of fiber, innervation, energy, and metabolism. Here, we summarize the contribution received at the time of publication of this Introductory Issue for the Special Issue dedicated to “Skeletal Muscle Atrophy: Mechanisms at a Cellular Level”. The Special Issue is divided into three sections. The first is dedicated to skeletal muscle pathophysiology, the second to disease mechanisms, and the third to therapeutic development. Full article

(This article belongs to the Special Issue Skeletal Muscle Atrophy: Mechanisms at a Cellular Level)

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Research

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21 pages, 10644 KiB

Open AccessArticle

VMP1 Regulated by chi-miR-124a Effects Goat Myoblast Proliferation, Autophagy, and Apoptosis through the PI3K/ULK1/mTOR Signaling Pathway

by Yufang Liu, Zuyang Zhou, Kunyu Li, Peng Wang, Yulin Chen, Shoulong Deng, Wenting Li, Kun Yu and Kejun Wang

Cells 2022, 11(14), 2227; https://doi.org/10.3390/cells11142227 - 18 Jul 2022

Cited by 7 | Viewed by 2591

Abstract

The production of goat meat is determined by the growth speed of muscle fibers, and the autophagy and apoptosis of myoblast cells is a crucial process in the growth of muscle fibers. The rapid growth of muscle fibers occurs from one month old [...] Read more.

The production of goat meat is determined by the growth speed of muscle fibers, and the autophagy and apoptosis of myoblast cells is a crucial process in the growth of muscle fibers. The rapid growth of muscle fibers occurs from one month old to nine months old in goats; however, the mechanisms of myoblast cells’ autophagy and apoptosis in this process are still unknown. To identify candidate genes and signaling pathway mechanisms involved in myoblast apoptosis and autophagy, we compared the expression characteristics of longissimus dorsi tissues from Wu’an goats—a native goat breed of China—at 1 month old (mon1 group) and 9 months old (mon9 group). Herein, a total of 182 differentially expressed mRNAs (DEGs) in the mon1 vs. mon9 comparison, along with the KEGG enrichments, showed that the PI3K-Akt pathway associated with autophagy and apoptosis was significantly enriched. Among these DEGs, expression of vacuole membrane protein 1 (VMP1)—a key gene for the PI3K-Akt pathway—was significantly upregulated in the older goats relative to the 1-month-old goats. We demonstrated that VMP1 promotes the proliferation and autophagy of myoblasts, and inhibits their apoptosis. The integration analysis of miRNA–mRNA showed that miR-124a was a regulator of VMP1 in muscle tissue, and overexpression and inhibition of miR-124a suppressed the proliferation and autophagy of myoblasts. The PI3K/Akt/mTOR pathway was an important pathway for cell autophagy. Additionally, the activator of the PI3K/Akt/mTOR pathway, the expression of VMP1, and ULK1 were higher than the negative control, and the expression of mTOR was depressed. The expression of VMP1, ULK1, and mTOR was the opposite when the inhibitor was added to the myoblasts. These results show that the PI3K/Akt/mTOR pathway promoted the expression of VMP1 and ULK1. By using adenovirus-mediated apoptosis and proliferation assays, we found that that miR-124a inhibits myoblast proliferation and autophagy, and promotes their apoptosis by targeting VMP1. In conclusion, our results indicated that VMP1 was highly expressed in the LD muscle tissues of nine-month-old goats, and that it was regulated by miR-124a to inhibit myoblast cells’ apoptosis through the PI3K/Akt/mTOR pathway, and to promote proliferation and autophagy. These findings contribute to the understanding of the molecular mechanisms involved in myoblast proliferation, autophagy, and apoptosis. Full article

(This article belongs to the Special Issue Skeletal Muscle Atrophy: Mechanisms at a Cellular Level)

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17 pages, 3585 KiB

Open AccessArticle

Leucine-Rich Diet Improved Muscle Function in Cachectic Walker 256 Tumour-Bearing Wistar Rats

by Laís Rosa Viana, Gabriela de Matuoka e Chiocchetti, Lucas Oroy, Willians Fernando Vieira, Estela Natacha Brandt Busanello, Ana Carolina Marques, Carla de Moraes Salgado, Alexandre Leite Rodrigues de Oliveira, André Schwambach Vieira, Paula Saenz Suarez, Lizandra Maia de Sousa, Bianca Gazieri Castelucci, Anibal Eugenio Vercesi, Sílvio Roberto Consonni and Maria Cristina Cintra Gomes-Marcondes

Cells 2021, 10(12), 3272; https://doi.org/10.3390/cells10123272 - 23 Nov 2021

Cited by 9 | Viewed by 3684

Abstract

Skeletal muscle atrophy occurs in several pathological conditions, such as cancer, especially during cancer-induced cachexia. This condition is associated with increased morbidity and poor treatment response, decreased quality of life, and increased mortality in cancer patients. A leucine-rich diet could be used as [...] Read more.

Skeletal muscle atrophy occurs in several pathological conditions, such as cancer, especially during cancer-induced cachexia. This condition is associated with increased morbidity and poor treatment response, decreased quality of life, and increased mortality in cancer patients. A leucine-rich diet could be used as a coadjutant therapy to prevent muscle atrophy in patients suffering from cancer cachexia. Besides muscle atrophy, muscle function loss is even more important to patient quality of life. Therefore, this study aimed to investigate the potential beneficial effects of leucine supplementation on whole-body functional/movement properties, as well as some markers of muscle breakdown and inflammatory status. Adult Wistar rats were randomly distributed into four experimental groups. Two groups were fed with a control diet (18% protein): Control (C) and Walker 256 tumour-bearing (W), and two other groups were fed with a leucine-rich diet (18% protein + 3% leucine): Leucine Control (L) and Leucine Walker 256 tumour-bearing (LW). A functional analysis (walking, behaviour, and strength tests) was performed before and after tumour inoculation. Cachexia parameters such as body weight loss, muscle and fat mass, pro-inflammatory cytokine profile, and molecular and morphological aspects of skeletal muscle were also determined. As expected, Walker 256 tumour growth led to muscle function decline, cachexia manifestation symptoms, muscle fibre cross-section area reduction, and classical muscle protein degradation pathway activation, with upregulation of FoxO1, MuRF-1, and 20S proteins. On the other hand, despite having no effect on the walking test, inflammation status or muscle oxidative capacity, the leucine-rich diet improved muscle strength and behaviour performance, maintained body weight, fat and muscle mass and decreased some protein degradation markers in Walker 256 tumour-bearing rats. Indeed, a leucine-rich diet alone could not completely revert cachexia but could potentially diminish muscle protein degradation, leading to better muscle functional performance in cancer cachexia. Full article

(This article belongs to the Special Issue Skeletal Muscle Atrophy: Mechanisms at a Cellular Level)

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14 pages, 4455 KiB

Open AccessArticle

Schisandrae chinensis Fructus Extract Ameliorates Muscle Atrophy in Streptozotocin-Induced Diabetic Mice by Downregulation of the CREB-KLF15 and Autophagy–Lysosomal Pathways

by Ho-Jung Choi, Myeong-Hoon Yeon and Hee-Sook Jun

Cells 2021, 10(9), 2283; https://doi.org/10.3390/cells10092283 - 2 Sep 2021

Cited by 14 | Viewed by 3664

Abstract

Type 1 diabetes mellitus is an autoimmune disease caused by the destruction of pancreatic beta cells. Many patients with type 1 diabetes experience skeletal muscle wasting. Although the link between type 1 diabetes and muscle wasting is not clearly known, insulin insufficiency and [...] Read more.

Type 1 diabetes mellitus is an autoimmune disease caused by the destruction of pancreatic beta cells. Many patients with type 1 diabetes experience skeletal muscle wasting. Although the link between type 1 diabetes and muscle wasting is not clearly known, insulin insufficiency and hyperglycemia may contribute to decreased muscle mass. In this study, we investigated the therapeutic effect of the ethanolic extract of Schisandrae chinensis Fructus (SFe) on muscle wasting in streptozotocin (STZ)-induced diabetic mice. STZ-diabetic C57BL/6 mice (blood glucose level ≥300 mg/dL) were orally administered SFe (250 or 500 mg/kg/day) for 6 weeks. We observed that SFe administration did not change blood glucose levels but increased gastrocnemius muscle weight, cross-sectional area, and grip strength in STZ-induced diabetic mice. Administration of SFe (500 mg/kg) decreased the expression of atrophic factors, such as MuRF1 and atrogin-1, but did not alter the expression of muscle synthetic factors. Further studies showed that SFe administration decreased the expression of KLF15 and p-CREB, which are upstream molecules of atrophic factors. Examination of the expression of molecules involved in autophagy–lysosomal pathways (e.g., p62/SQSTM1, Atg7, Beclin-1, ULK-1, LC3-I, and LC3-II) revealed that SFe administration significantly decreased the expression of p62/SQSTM1, LC3-I, and LC3-II; however, no changes were observed in the expression of Atg7, Beclin-1, or ULK-1. Our results suggest that SFe ameliorated muscle wasting in STZ-induced diabetic mice by decreasing protein degradation via downregulation of the CREB-KLF15-mediated UPS system and the p62/SQSTM1-mediated autophagy–lysosomal pathway. Full article

(This article belongs to the Special Issue Skeletal Muscle Atrophy: Mechanisms at a Cellular Level)

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22 pages, 8042 KiB

Open AccessArticle

Concurrent BMP Signaling Maintenance and TGF-β Signaling Inhibition Is a Hallmark of Natural Resistance to Muscle Atrophy in the Hibernating Bear

by Laura Cussonneau, Christian Boyer, Charlotte Brun, Christiane Deval, Emmanuelle Loizon, Emmanuelle Meugnier, Elise Gueret, Emeric Dubois, Daniel Taillandier, Cécile Polge, Daniel Béchet, Guillemette Gauquelin-Koch, Alina L. Evans, Jon M. Arnemo, Jon E. Swenson, Stéphane Blanc, Chantal Simon, Etienne Lefai, Fabrice Bertile and Lydie Combaret

Cells 2021, 10(8), 1873; https://doi.org/10.3390/cells10081873 - 23 Jul 2021

Cited by 8 | Viewed by 4309

Abstract

Muscle atrophy arises from a multiplicity of physio-pathological situations and has very detrimental consequences for the whole body. Although knowledge of muscle atrophy mechanisms keeps growing, there is still no proven treatment to date. This study aimed at identifying new drivers for muscle [...] Read more.

Muscle atrophy arises from a multiplicity of physio-pathological situations and has very detrimental consequences for the whole body. Although knowledge of muscle atrophy mechanisms keeps growing, there is still no proven treatment to date. This study aimed at identifying new drivers for muscle atrophy resistance. We selected an innovative approach that compares muscle transcriptome between an original model of natural resistance to muscle atrophy, the hibernating brown bear, and a classical model of induced atrophy, the unloaded mouse. Using RNA sequencing, we identified 4415 differentially expressed genes, including 1746 up- and 2369 down-regulated genes, in bear muscles between the active versus hibernating period. We focused on the Transforming Growth Factor (TGF)-β and the Bone Morphogenetic Protein (BMP) pathways, respectively, involved in muscle mass loss and maintenance. TGF-β- and BMP-related genes were overall down- and up-regulated in the non-atrophied muscles of the hibernating bear, respectively, and the opposite occurred for the atrophied muscles of the unloaded mouse. This was further substantiated at the protein level. Our data suggest TGF-β/BMP balance is crucial for muscle mass maintenance during long-term physical inactivity in the hibernating bear. Thus, concurrent activation of the BMP pathway may potentiate TGF-β inhibiting therapies already targeted to prevent muscle atrophy. Full article

(This article belongs to the Special Issue Skeletal Muscle Atrophy: Mechanisms at a Cellular Level)

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13 pages, 3670 KiB

Open AccessArticle

NeuroHeal Improves Muscle Regeneration after Injury

by Sara Marmolejo-Martínez-Artesero, David Romeo-Guitart, Vanesa Venegas, Mario Marotta and Caty Casas

Cells 2021, 10(1), 22; https://doi.org/10.3390/cells10010022 - 24 Dec 2020

Cited by 3 | Viewed by 3479

Abstract

Musculoskeletal injuries represent a challenging medical problem. Although the skeletal muscle is able to regenerate and recover after injury, the process engaged with conservative therapy can be inefficient, leading to a high re-injury rate. In addition, the formation of scar tissue implies an [...] Read more.

Musculoskeletal injuries represent a challenging medical problem. Although the skeletal muscle is able to regenerate and recover after injury, the process engaged with conservative therapy can be inefficient, leading to a high re-injury rate. In addition, the formation of scar tissue implies an alteration of mechanical properties in muscle. There is still a need for new treatments of the injured muscle. NeuroHeal may be one option. Published studies demonstrated that it reduces muscle atrophy due to denervation and disuse. The main objective of the present work was to assess the potential of NeuroHeal to improve muscle regeneration after traumatic injury. Secondary objectives included characterizing the effect of NeuroHeal treatment on satellite cell biology. We used a rat model of sport-induced injury in the gastrocnemius and analyzed the effects of NeuroHeal on functional recovery by means of electrophysiology and tetanic force analysis. These studies were accompanied by immunohistochemistry of the injured muscle to analyze fibrosis, satellite cell state, and fiber type. In addition, we used an in vitro model to determine the effect of NeuroHeal on myoblast biology and partially decipher its mechanism of action. The results showed that NeuroHeal treatment advanced muscle fiber recovery after injury in a preclinical model of muscle injury, and significantly reduced the formation of scar tissue. In vitro, we observed that NeuroHeal accelerated the formation of myotubes. The results pave the way for novel therapeutic avenues for muscle/tendinous disorders. Full article

(This article belongs to the Special Issue Skeletal Muscle Atrophy: Mechanisms at a Cellular Level)

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15 pages, 1374 KiB

Open AccessArticle

Leucine Supplementation Decreases HDAC4 Expression and Nuclear Localization in Skeletal Muscle Fiber of Rats Submitted to Hindlimb Immobilization

by Paula K. N. Alves, André Cruz, William J. Silva, Siegfried Labeit and Anselmo S. Moriscot

Cells 2020, 9(12), 2582; https://doi.org/10.3390/cells9122582 - 2 Dec 2020

Cited by 5 | Viewed by 2444

Abstract

In this study we surveyed a rat skeletal muscle RNA-Seq for genes that are induced by hindlimb immobilization and, in turn, become attenuated by leucine supplementation. This approach, in search of leucine-atrophy protection mediating genes, identified histone deacetylase 4 (HDAC4) as [...] Read more.

In this study we surveyed a rat skeletal muscle RNA-Seq for genes that are induced by hindlimb immobilization and, in turn, become attenuated by leucine supplementation. This approach, in search of leucine-atrophy protection mediating genes, identified histone deacetylase 4 (HDAC4) as highly responsive to both hindlimb immobilization and leucine supplementation. We then examined the impact of leucine on HDAC4 expression, tissue localization, and target genes. A total of 76 male Wistar rats (~280 g) were submitted to hindlimb immobilization and/or leucine supplementation for 3, 7 and 12 days. These animals were euthanized, and soleus muscle was removed for further analysis. RNA-Seq analysis of hindlimb immobilized rats indicated a sharp induction (log2 = 3.4) of HDAC4 expression which was attenuated by leucine supplementation (~50%). Real-time PCR and protein expression analysis by Western blot confirmed increased HDAC4 mRNA after 7 days of hindlimb immobilization and mitigation of induction by leucine supplementation. Regarding the HDAC4 localization, the proportion of positive nuclei was higher in the immobilized group and decreased after leucine supplementation. Also, we found a marked decrease of myogenin and MAFbx-atrogin-1 mRNA levels upon leucine supplementation, while CAMKII and DACH2 mRNA levels were increased by leucine supplementation. Our data suggest that HDAC4 inhibition might be involved in the anti-atrophic effects of leucine. Full article

(This article belongs to the Special Issue Skeletal Muscle Atrophy: Mechanisms at a Cellular Level)

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15 pages, 1825 KiB

Open AccessArticle

Small-Molecule Chemical Knockdown of MuRF1 in Melanoma Bearing Mice Attenuates Tumor Cachexia Associated Myopathy

by Volker Adams, Victoria Gußen, Sergey Zozulya, André Cruz, Anselmo Moriscot, Axel Linke and Siegfried Labeit

Cells 2020, 9(10), 2272; https://doi.org/10.3390/cells9102272 - 11 Oct 2020

Cited by 20 | Viewed by 4277

Abstract

Patients with malignant tumors frequently suffer during disease progression from a syndrome referred to as cancer cachexia (CaCax): CaCax includes skeletal muscle atrophy and weakness, loss of bodyweight, and fat tissues. Currently, there are no FDA (Food and Drug Administration) approved treatments available [...] Read more.

Patients with malignant tumors frequently suffer during disease progression from a syndrome referred to as cancer cachexia (CaCax): CaCax includes skeletal muscle atrophy and weakness, loss of bodyweight, and fat tissues. Currently, there are no FDA (Food and Drug Administration) approved treatments available for CaCax. Here, we studied skeletal muscle atrophy and dysfunction in a murine CaCax model by injecting B16F10 melanoma cells into mouse thighs and followed mice during melanoma outgrowth. Skeletal muscles developed progressive weakness as detected by wire hang tests (WHTs) during days 13–23. Individual muscles analyzed at day 24 had atrophy, mitochondrial dysfunction, augmented metabolic reactive oxygen species (ROS) stress, and a catabolically activated ubiquitin proteasome system (UPS), including upregulated MuRF1. Accordingly, we tested as an experimental intervention of recently identified small molecules, Myomed-205 and -946, that inhibit MuRF1 activity and MuRF1/MuRF2 expression. Results indicate that MuRF1 inhibitor fed attenuated induction of MuRF1 in tumor stressed muscles. In addition, the compounds augmented muscle performance in WHTs and attenuated muscle weight loss. Myomed-205 and -946 also rescued citrate synthase and complex-1 activities in tumor-stressed muscles, possibly suggesting that mitochondrial-metabolic and muscle wasting effects in this CaCax model are mechanistically connected. Inhibition of MuRF1 during tumor cachexia may represent a suitable strategy to attenuate skeletal muscle atrophy and dysfunction. Full article

(This article belongs to the Special Issue Skeletal Muscle Atrophy: Mechanisms at a Cellular Level)

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17 pages, 3681 KiB

Open AccessArticle

NeuroHeal Reduces Muscle Atrophy and Modulates Associated Autophagy

by Sara Marmolejo-Martínez-Artesero, David Romeo-Guitart, Laura Mañas-García, Esther Barreiro and Caty Casas

Cells 2020, 9(7), 1575; https://doi.org/10.3390/cells9071575 - 28 Jun 2020

Cited by 6 | Viewed by 4023

Abstract

Muscle wasting is an unmet medical need which leads to a reduction of myofiber diameter and a negative impact on the functional performance of daily activities. We previously found that a new neuroprotective drug called NeuroHeal reduced muscle atrophy produced by transient denervation. [...] Read more.

Muscle wasting is an unmet medical need which leads to a reduction of myofiber diameter and a negative impact on the functional performance of daily activities. We previously found that a new neuroprotective drug called NeuroHeal reduced muscle atrophy produced by transient denervation. Aiming to decipher whether NeuroHeal has a direct role in muscle biology, we used herein different models of muscle atrophy: one caused by chronic denervation, another caused by hindlimb immobilization, and lastly, an in vitro model of myotube atrophy with Tumor Necrosis Factor-α (TNFα). In all these models, we observed that NeuroHeal reduced muscle atrophy and that SIRT1 activation seems to be required for that. The treatment downregulated some critical markers of protein degradation: Muscle Ring Finger 1 (MuRF1), K48 poly-Ub chains, and p62/SQSTM1. Moreover, it seems to restore the autophagy flux associated with denervation. Hence, we envisage a prospective use of NeuroHeal at clinics for different myopathies. Full article

(This article belongs to the Special Issue Skeletal Muscle Atrophy: Mechanisms at a Cellular Level)

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Review

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22 pages, 1569 KiB

Open AccessReview

Metabolic Pathways and Ion Channels Involved in Skeletal Muscle Atrophy: A Starting Point for Potential Therapeutic Strategies

by Ileana Canfora, Nancy Tarantino and Sabata Pierno

Cells 2022, 11(16), 2566; https://doi.org/10.3390/cells11162566 - 18 Aug 2022

Cited by 7 | Viewed by 3858

Abstract

Skeletal muscle tissue has the important function of supporting and defending the organism. It is the largest apparatus in the human body, and its function is important for contraction and movements. In addition, it is involved in the regulation of protein synthesis and [...] Read more.

Skeletal muscle tissue has the important function of supporting and defending the organism. It is the largest apparatus in the human body, and its function is important for contraction and movements. In addition, it is involved in the regulation of protein synthesis and degradation. In fact, inhibition of protein synthesis and/or activation of catabolism determines a pathological condition called muscle atrophy. Muscle atrophy is a reduction in muscle mass resulting in a partial or complete loss of function. It has been established that many physiopathological conditions can cause a reduction in muscle mass. Nevertheless, it is not well known the molecular mechanisms and signaling processes causing this dramatic event. There are multiple concomitant processes involved in muscle atrophy. In fact, the gene transcription of some factors, oxidative stress mechanisms, and the alteration of ion transport through specific ion channels may contribute to muscle function impairment. In this review, we focused on the molecular mechanisms responsible for muscle damage and potential drugs to be used to alleviate this disabling condition. Full article

(This article belongs to the Special Issue Skeletal Muscle Atrophy: Mechanisms at a Cellular Level)

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16 pages, 725 KiB

Open AccessReview

Skeletal Muscle Pathogenesis in Polyglutamine Diseases

by Caterina Marchioretti, Emanuela Zuccaro, Udai Bhan Pandey, Jessica Rosati, Manuela Basso and Maria Pennuto

Cells 2022, 11(13), 2105; https://doi.org/10.3390/cells11132105 - 3 Jul 2022

Cited by 2 | Viewed by 4083

Abstract

Polyglutamine diseases are characterized by selective dysfunction and degeneration of specific types of neurons in the central nervous system. In addition, nonneuronal cells can also be affected as a consequence of primary degeneration or due to neuronal dysfunction. Skeletal muscle is a primary [...] Read more.

Polyglutamine diseases are characterized by selective dysfunction and degeneration of specific types of neurons in the central nervous system. In addition, nonneuronal cells can also be affected as a consequence of primary degeneration or due to neuronal dysfunction. Skeletal muscle is a primary site of toxicity of polyglutamine-expanded androgen receptor, but it is also affected in other polyglutamine diseases, more likely due to neuronal dysfunction and death. Nonetheless, pathological processes occurring in skeletal muscle atrophy impact the entire body metabolism, thus actively contributing to the inexorable progression towards the late and final stages of disease. Skeletal muscle atrophy is well recapitulated in animal models of polyglutamine disease. In this review, we discuss the impact and relevance of skeletal muscle in patients affected by polyglutamine diseases and we review evidence obtained in animal models and patient-derived cells modeling skeletal muscle. Full article

(This article belongs to the Special Issue Skeletal Muscle Atrophy: Mechanisms at a Cellular Level)

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18 pages, 1727 KiB

Open AccessReview

Protein Arginine Methyltransferases in Neuromuscular Function and Diseases

by Jinwoo Lee, Subin An, Sang-Jin Lee and Jong-Sun Kang

Cells 2022, 11(3), 364; https://doi.org/10.3390/cells11030364 - 21 Jan 2022

Cited by 10 | Viewed by 3715 | Correction

Abstract

Neuromuscular diseases (NMDs) are characterized by progressive loss of muscle mass and strength that leads to impaired body movement. It not only severely diminishes the quality of life of the patients, but also subjects them to increased risk of secondary medical conditions such [...] Read more.

Neuromuscular diseases (NMDs) are characterized by progressive loss of muscle mass and strength that leads to impaired body movement. It not only severely diminishes the quality of life of the patients, but also subjects them to increased risk of secondary medical conditions such as fall-induced injuries and various chronic diseases. However, no effective treatment is currently available to prevent or reverse the disease progression. Protein arginine methyltransferases (PRMTs) are emerging as a potential therapeutic target for diverse diseases, such as cancer and cardiovascular diseases. Their expression levels are altered in the patients and molecular mechanisms underlying the association between PRMTs and the diseases are being investigated. PRMTs have been shown to regulate development, homeostasis, and regeneration of both muscle and neurons, and their association to NMDs are emerging as well. Through inhibition of PRMT activities, a few studies have reported suppression of cytotoxic phenotypes observed in NMDs. Here, we review our current understanding of PRMTs’ involvement in the pathophysiology of NMDs and potential therapeutic strategies targeting PRMTs to address the unmet medical need. Full article

(This article belongs to the Special Issue Skeletal Muscle Atrophy: Mechanisms at a Cellular Level)

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37 pages, 1907 KiB

Open AccessFeature PaperReview

Master Regulators of Muscle Atrophy: Role of Costamere Components

by Luisa Gorza, Matteo Sorge, Laura Seclì and Mara Brancaccio

Cells 2021, 10(1), 61; https://doi.org/10.3390/cells10010061 - 3 Jan 2021

Cited by 20 | Viewed by 9136

Abstract

The loss of muscle mass and force characterizes muscle atrophy in several different conditions, which share the expression of atrogenes and the activation of their transcriptional regulators. However, attempts to antagonize muscle atrophy development in different experimental contexts by targeting contributors to the [...] Read more.

The loss of muscle mass and force characterizes muscle atrophy in several different conditions, which share the expression of atrogenes and the activation of their transcriptional regulators. However, attempts to antagonize muscle atrophy development in different experimental contexts by targeting contributors to the atrogene pathway showed partial effects in most cases. Other master regulators might independently contribute to muscle atrophy, as suggested by our recent evidence about the co-requirement of the muscle-specific chaperone protein melusin to inhibit unloading muscle atrophy development. Furthermore, melusin and other muscle mass regulators, such as nNOS, belong to costameres, the macromolecular complexes that connect sarcolemma to myofibrils and to the extracellular matrix, in correspondence with specific sarcomeric sites. Costameres sense a mechanical load and transduce it both as lateral force and biochemical signals. Recent evidence further broadens this classic view, by revealing the crucial participation of costameres in a sarcolemmal “signaling hub” integrating mechanical and humoral stimuli, where mechanical signals are coupled with insulin and/or insulin-like growth factor stimulation to regulate muscle mass. Therefore, this review aims to enucleate available evidence concerning the early involvement of costamere components and additional putative master regulators in the development of major types of muscle atrophy. Full article

(This article belongs to the Special Issue Skeletal Muscle Atrophy: Mechanisms at a Cellular Level)

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40 pages, 2615 KiB

Open AccessFeature PaperReview

Nutraceuticals and Exercise against Muscle Wasting during Cancer Cachexia

by Giorgio Aquila, Andrea David Re Cecconi, Jeffrey J. Brault, Oscar Corli and Rosanna Piccirillo

Cells 2020, 9(12), 2536; https://doi.org/10.3390/cells9122536 - 24 Nov 2020

Cited by 28 | Viewed by 7907

Abstract

Cancer cachexia (CC) is a debilitating multifactorial syndrome, involving progressive deterioration and functional impairment of skeletal muscles. It affects about 80% of patients with advanced cancer and causes premature death. No causal therapy is available against CC. In the last few decades, our [...] Read more.

Cancer cachexia (CC) is a debilitating multifactorial syndrome, involving progressive deterioration and functional impairment of skeletal muscles. It affects about 80% of patients with advanced cancer and causes premature death. No causal therapy is available against CC. In the last few decades, our understanding of the mechanisms contributing to muscle wasting during cancer has markedly increased. Both inflammation and oxidative stress (OS) alter anabolic and catabolic signaling pathways mostly culminating with muscle depletion. Several preclinical studies have emphasized the beneficial roles of several classes of nutraceuticals and modes of physical exercise, but their efficacy in CC patients remains scant. The route of nutraceutical administration is critical to increase its bioavailability and achieve the desired anti-cachexia effects. Accumulating evidence suggests that a single therapy may not be enough, and a bimodal intervention (nutraceuticals plus exercise) may be a more effective treatment for CC. This review focuses on the current state of the field on the role of inflammation and OS in the pathogenesis of muscle atrophy during CC, and how nutraceuticals and physical activity may act synergistically to limit muscle wasting and dysfunction. Full article

(This article belongs to the Special Issue Skeletal Muscle Atrophy: Mechanisms at a Cellular Level)

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