Special Issue "Skeletal Muscle Atrophy: Mechanisms at a Cellular Level"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: 1 September 2021.

Special Issue Editors

Dr. Maria Pennuto
E-Mail Website
Guest Editor
Department of Biomedical Sciences, University of Padova, Italy
Interests: neurodegenerative diseases; androgens; polyglutamine; metabolism; skeletal muscle
Dr. Marco Pirazzini
E-Mail Website
Guest Editor
Department of Biomedical Sciences, University of Padova, Italy
Interests: neurotoxins; muscle paralysis; neuromuscular junction; neuromuscular disorders; nerve regeneration

Special Issue Information

Dear Colleagues,

Skeletal muscles constitute the largest body organ, making up about half of a mammal’s bodyweight. Several conditions, including neuromuscular disorders, aging, cancer, and those associated with toxins, can lead to losses in muscle mass and function. This acquired condition, referred to as muscle atrophy, is an emerging health concern and a burden for human health. The cellular and molecular factors involved in muscle atrophy are still relatively unknown, despite great effort being made over the last two decades to decipher the pathophysiological bases underlying muscle loss. A wide range of cellular (e.g., myocites and satellite cells) and subcellular (e.g., neuromuscular junctions) compartments, organelles (e.g., mitochondria, ER, SR), degradation pathways (e.g., UPS and autophagy), molecular signaling networks (e.g., AKT, mTOR, etc.), and genes (e.g., atrogenes) have been identified as critical players in the regulation of muscle mass and atrophy and may play roles in the plasticity and vulnerability of muscle tissue under physiological and pathological conditions.

This Special Issue of Cells aims to provide a general overview of the cellular and molecular mechanisms responsible for muscle atrophy and to stimulate the identification of novel strategies to tackle conditions or disorders associated with muscle loss.

We look forward to your contributions.

Dr. Maria Pennuto
Dr. Marco Pirazzini
Guest Editors

Manuscript Submission Information

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Keywords

  • muscle atrophy
  • muscle proteostasis
  • muscle disuse
  • atrogenes
  • sarcopenia
  • neuromuscular disorder
  • myopathies
  • muscle degeneration
  • neuromuscular paralysis
  • cancer cachexia

Published Papers (6 papers)

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Research

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Article
NeuroHeal Improves Muscle Regeneration after Injury
Cells 2021, 10(1), 22; https://doi.org/10.3390/cells10010022 - 24 Dec 2020
Viewed by 715
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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Article
Leucine Supplementation Decreases HDAC4 Expression and Nuclear Localization in Skeletal Muscle Fiber of Rats Submitted to Hindlimb Immobilization
Cells 2020, 9(12), 2582; https://doi.org/10.3390/cells9122582 - 02 Dec 2020
Viewed by 463
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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Article
Small-Molecule Chemical Knockdown of MuRF1 in Melanoma Bearing Mice Attenuates Tumor Cachexia Associated Myopathy
Cells 2020, 9(10), 2272; https://doi.org/10.3390/cells9102272 - 11 Oct 2020
Cited by 4 | Viewed by 745
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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Article
NeuroHeal Reduces Muscle Atrophy and Modulates Associated Autophagy
Cells 2020, 9(7), 1575; https://doi.org/10.3390/cells9071575 - 28 Jun 2020
Cited by 2 | Viewed by 1021
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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Review
Master Regulators of Muscle Atrophy: Role of Costamere Components
Cells 2021, 10(1), 61; https://doi.org/10.3390/cells10010061 - 03 Jan 2021
Cited by 2 | Viewed by 1468
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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Review
Nutraceuticals and Exercise against Muscle Wasting during Cancer Cachexia
Cells 2020, 9(12), 2536; https://doi.org/10.3390/cells9122536 - 24 Nov 2020
Cited by 3 | Viewed by 1195
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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Planned Papers

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

Title: Protein arginine methyltransferases in skeletal muscle and neuromuscular function
Authors: Jong-sun Kang
Affiliation: SungKyunKwan University, Suwon, South Korea

Title: Future use of myostatin – learning from the past
Authors: John Vissing
Affiliation: Department of Neurology, University of Copenhagen, Copenhagen, Denmark

Title: Insights into muscle atrophy from mass spectrometry profiling: Common properties of myocellular proteomes under stress
Authors: Siegfried Labeit
Affiliation: Medical Faculty Mannheim, University of Heidelberg, Germany

Title: Small-molecule chemical knock-down of MuRF1 in melanoma bearing mice attenuates tumor cachexia associated myopathy
Authors: Volker Adams; Victoria Gußen; Sergey Zozulya; Andre Cruz; Anselmo Moriscot; Axel Linke; Siegfried Labeit
Affiliation: University of Heidelberg, Germany
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 body weight, and fat tissues. Currently, there are no FDA 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 following 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 ROS stress, and a catabolically activated UPS system, including upregulated MuRF1. Accordingly, we tested as an experimental intervention recently identified small molecules Myomed#205 and #946 that target the E3 ligase MuRF1. Results indicate that MuRF1 inhibitor feeding attenuated induction of MuRF1 in tumor stressed muscles. In addition, compounds augmented muscle performance in WHTs and attenuated muscle weight loss. Myomed#205 and #946 also rescued citrate synthase and succinate dehydrogenase levels in tumor-stressed muscles, possibly suggesting that 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.

Title: Master regulators of muscle atrophy: role of costamere components
Authors: Luisa Gorza; Mara Brancaccio
Affiliation: Università degli Studi di Padova, Padua, Italy

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