International Journal of Molecular Sciences

Editorial

Jump to: Research, Review

3 pages, 179 KiB

Open AccessEditorial

Muscle Atrophy: From Bench to Bedside

by Daniel Taillandier

Int. J. Mol. Sci. 2023, 24(8), 7551; https://doi.org/10.3390/ijms24087551 - 20 Apr 2023

Viewed by 997

Abstract

The loss of muscle mass is a common adaptation to some physiological situations (e [...] Full article

(This article belongs to the Special Issue Muscle Atrophy: From Bench to Bedside)

Research

Jump to: Editorial, Review

15 pages, 5429 KiB

Open AccessArticle

Role of p53 in Cisplatin-Induced Myotube Atrophy

by Chinami Matsumoto, Hitomi Sekine, Nana Zhang, Sachiko Mogami, Naoki Fujitsuka and Hiroshi Takeda

Int. J. Mol. Sci. 2023, 24(11), 9176; https://doi.org/10.3390/ijms24119176 - 24 May 2023

Cited by 1 | Viewed by 1544

Abstract

Chemotherapy-induced sarcopenia is an unfavorable prognostic factor implicated in the development of postoperative complications and reduces the quality of life of patients with cancer. Skeletal muscle loss due to cisplatin use is caused by mitochondrial dysfunction and activation of muscle-specific ubiquitin ligases Atrogin-1 [...] Read more.

Chemotherapy-induced sarcopenia is an unfavorable prognostic factor implicated in the development of postoperative complications and reduces the quality of life of patients with cancer. Skeletal muscle loss due to cisplatin use is caused by mitochondrial dysfunction and activation of muscle-specific ubiquitin ligases Atrogin-1 and muscle RING finger 1 (MuRF1). Although animal studies suggest the involvement of p53 in age-, immobility-, and denervation-related muscle atrophy, the association between cisplatin-induced atrophy and p53 remains unknown. Herein, we investigated the effect of a p53-specific inhibitor, pifithrin-alpha (PFT-α), on cisplatin-induced atrophy in C2C12 myotubes. Cisplatin increased the protein levels of p53, phosphorylated p53, and upregulated the mRNA expression of p53 target genes PUMA and p21 in C2C12 myotubes. PFT-α ameliorated the increase in intracellular reactive oxygen species production and mitochondrial dysfunction, and also reduced the cisplatin-induced increase in the Bax/Bcl-2 ratio. Although PFT-α also reduced the cisplatin-induced increase in MuRF1 and Atrogin-1 gene expression, it did not ameliorate the decrease in myosin heavy chain mRNA and protein levels and muscle-specific actin and myoglobin protein levels. We conclude that cisplatin increases muscle degradation in C2C12 myotubes in a p53-dependent manner, but p53 has minimal involvement in the reduction of muscle protein synthesis. Full article

(This article belongs to the Special Issue Muscle Atrophy: From Bench to Bedside)

► Show Figures

Figure 1

18 pages, 3100 KiB

Open AccessArticle

Induction of ATF4-Regulated Atrogenes Is Uncoupled from Muscle Atrophy during Disuse in Halofuginone-Treated Mice and in Hibernating Brown Bears

by Laura Cussonneau, Cécile Coudy-Gandilhon, Christiane Deval, Ghita Chaouki, Mehdi Djelloul-Mazouz, Yoann Delorme, Julien Hermet, Guillemette Gauquelin-Koch, Cécile Polge, Daniel Taillandier, Julien Averous, Alain Bruhat, Céline Jousse, Isabelle Papet, Fabrice Bertile, Etienne Lefai, Pierre Fafournoux, Anne-Catherine Maurin and Lydie Combaret

Int. J. Mol. Sci. 2023, 24(1), 621; https://doi.org/10.3390/ijms24010621 - 30 Dec 2022

Cited by 1 | Viewed by 1777

Abstract

Activating transcription factor 4 (ATF4) is involved in muscle atrophy through the overexpression of some atrogenes. However, it also controls the transcription of genes involved in muscle homeostasis maintenance. Here, we explored the effect of ATF4 activation by the pharmacological molecule halofuginone during [...] Read more.

Activating transcription factor 4 (ATF4) is involved in muscle atrophy through the overexpression of some atrogenes. However, it also controls the transcription of genes involved in muscle homeostasis maintenance. Here, we explored the effect of ATF4 activation by the pharmacological molecule halofuginone during hindlimb suspension (HS)-induced muscle atrophy. Firstly, we reported that periodic activation of ATF4-regulated atrogenes (Gadd45a, Cdkn1a, and Eif4ebp1) by halofuginone was not associated with muscle atrophy in healthy mice. Secondly, halofuginone-treated mice even showed reduced atrophy during HS, although the induction of the ATF4 pathway was identical to that in untreated HS mice. We further showed that halofuginone inhibited transforming growth factor-β (TGF-β) signalling, while promoting bone morphogenetic protein (BMP) signalling in healthy mice and slightly preserved protein synthesis during HS. Finally, ATF4-regulated atrogenes were also induced in the atrophy-resistant muscles of hibernating brown bears, in which we previously also reported concurrent TGF-β inhibition and BMP activation. Overall, we show that ATF4-induced atrogenes can be uncoupled from muscle atrophy. In addition, our data also indicate that halofuginone can control the TGF-β/BMP balance towards muscle mass maintenance. Whether halofuginone-induced BMP signalling can counteract the effect of ATF4-induced atrogenes needs to be further investigated and may open a new avenue to fight muscle atrophy. Finally, our study opens the way for further studies to identify well-tolerated chemical compounds in humans that are able to fine-tune the TGF-β/BMP balance and could be used to preserve muscle mass during catabolic situations. Full article

(This article belongs to the Special Issue Muscle Atrophy: From Bench to Bedside)

► Show Figures

Figure 1

11 pages, 1567 KiB

Open AccessArticle

Activation of Transposable Elements in Human Skeletal Muscle Fibers upon Statin Treatment

by Braulio Valdebenito-Maturana, Franco Valdebenito-Maturana, Mónica Carrasco, Juan Carlos Tapia and Alejandro Maureira

Int. J. Mol. Sci. 2023, 24(1), 244; https://doi.org/10.3390/ijms24010244 - 23 Dec 2022

Cited by 3 | Viewed by 1602

Abstract

High cholesterol levels have been linked to a high risk of cardiovascular diseases, and preventative pharmacological care to lower cholesterol levels is critically important. Statins, which are hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are drugs used to reduce the endogenous cholesterol synthesis, thus minimizing [...] Read more.

High cholesterol levels have been linked to a high risk of cardiovascular diseases, and preventative pharmacological care to lower cholesterol levels is critically important. Statins, which are hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are drugs used to reduce the endogenous cholesterol synthesis, thus minimizing its pathophysiological effects. Despite the proven benefits, statins therapy is known to cause a number of skeletal muscle disorders, including myalgia, myopathy and myositis. The mechanisms underlying such statin-induced side effects are unknown. Recently, a group of genes and molecular pathways has been described to participate in statin-induced myopathy, caused by either simvastatin or rosuvastatin, although the mechanism by which changes in gene regulation occur was not studied. Transposable Elements (TEs), repetitive elements that move within the genome, are known to play regulatory roles in gene expression; however, their role in statin-induced muscle damage has not been studied. We analyzed the expression of TEs in human skeletal fiber cells treated with either simvastatin or rosuvastatin, as well as their respective controls, and identified TEs that change their expression in response to the treatment. We found that simvastatin resulted in >1000 differentially expressed (DE) TEs, whereas rosuvastatin resulted in only 27 DE TEs. Using network analysis tools, we predicted the impact of the DE TEs on the expression of genes and found that amongst the genes potentially modulated by TEs, there are some previously associated to statin-linked myopathy pathways (e.g., AKT3). Overall, our results indicate that TEs may be a key player in the statin-induced muscle side effects. Full article

(This article belongs to the Special Issue Muscle Atrophy: From Bench to Bedside)

► Show Figures

Figure 1

21 pages, 3429 KiB

Open AccessArticle

Empagliflozin Preserves Skeletal Muscle Function in a HFpEF Rat Model

by Ephraim B. Winzer, Antje Schauer, Erik Langner, Antje Augstein, Keita Goto, Anita Männel, Peggy Barthel, Anett Jannasch, Siegfried Labeit, Norman Mangner, Axel Linke and Volker Adams

Int. J. Mol. Sci. 2022, 23(19), 10989; https://doi.org/10.3390/ijms231910989 - 20 Sep 2022

Cited by 11 | Viewed by 2723

Abstract

Besides structural alterations in the myocardium, heart failure with preserved ejection fraction (HFpEF) is also associated with molecular and physiological alterations of the peripheral skeletal muscles (SKM) contributing to exercise intolerance often seen in HFpEF patients. Recently, the use of Sodium-Glucose-Transporter 2 inhibitors [...] Read more.

Besides structural alterations in the myocardium, heart failure with preserved ejection fraction (HFpEF) is also associated with molecular and physiological alterations of the peripheral skeletal muscles (SKM) contributing to exercise intolerance often seen in HFpEF patients. Recently, the use of Sodium-Glucose-Transporter 2 inhibitors (SGLT2i) in clinical studies provided evidence for a significant reduction in the combined risk of cardiovascular death or hospitalization for HFpEF. The present study aimed to further elucidate the impact of Empagliflozin (Empa) on: (1) SKM function and metabolism and (2) mitochondrial function in an established HFpEF rat model. At the age of 24 weeks, obese ZSF1 rats were randomized either receiving standard care or Empa in the drinking water. ZSF1 lean animals served as healthy controls. After 8 weeks of treatment, echocardiography and SKM contractility were performed. Mitochondrial function was assessed in saponin skinned fibers and SKM tissue was snap frozen for molecular analyses. HFpEF was evident in the obese animals when compared to lean—increased E/é and preserved left ventricular ejection fraction. Empa treatment significantly improved E/é and resulted in improved SKM contractility with reduced intramuscular lipid content. Better mitochondrial function (mainly in complex IV) with only minor modulation of atrophy-related proteins was seen after Empa treatment. The results clearly documented a beneficial effect of Empa on SKM function in the present HFpEF model. These effects were accompanied by positive effects on mitochondrial function possibly modulating SKM function. Full article

(This article belongs to the Special Issue Muscle Atrophy: From Bench to Bedside)

► Show Figures

Figure 1

Review

Jump to: Editorial, Research

14 pages, 1159 KiB

Open AccessReview

Sepsis-Associated Muscle Wasting: A Comprehensive Review from Bench to Bedside

by Ikumi Yoshihara, Yutaka Kondo, Ken Okamoto and Hiroshi Tanaka

Int. J. Mol. Sci. 2023, 24(5), 5040; https://doi.org/10.3390/ijms24055040 - 6 Mar 2023

Cited by 3 | Viewed by 4501

Abstract

Sepsis-associated muscle wasting (SAMW) is characterized by decreased muscle mass, reduced muscle fiber size, and decreased muscle strength, resulting in persistent physical disability accompanied by sepsis. Systemic inflammatory cytokines are the main cause of SAMW, which occurs in 40–70% of patients with sepsis. [...] Read more.

Sepsis-associated muscle wasting (SAMW) is characterized by decreased muscle mass, reduced muscle fiber size, and decreased muscle strength, resulting in persistent physical disability accompanied by sepsis. Systemic inflammatory cytokines are the main cause of SAMW, which occurs in 40–70% of patients with sepsis. The pathways associated with the ubiquitin–proteasome and autophagy systems are particularly activated in the muscle tissues during sepsis and may lead to muscle wasting. Additionally, expression of muscle atrophy-related genes Atrogin-1 and MuRF-1 are seemingly increased via the ubiquitin–proteasome pathway. In clinical settings, electrical muscular stimulation, physiotherapy, early mobilization, and nutritional support are used for patients with sepsis to prevent or treat SAMW. However, there are no pharmacological treatments for SAMW, and the underlying mechanisms are still unknown. Therefore, research is urgently required in this field. Full article

(This article belongs to the Special Issue Muscle Atrophy: From Bench to Bedside)

► Show Figures

Figure 1

47 pages, 2964 KiB

Open AccessReview

Fiber-Type Shifting in Sarcopenia of Old Age: Proteomic Profiling of the Contractile Apparatus of Skeletal Muscles

by Paul Dowling, Stephen Gargan, Dieter Swandulla and Kay Ohlendieck

Int. J. Mol. Sci. 2023, 24(3), 2415; https://doi.org/10.3390/ijms24032415 - 26 Jan 2023

Cited by 20 | Viewed by 6665

Abstract

The progressive loss of skeletal muscle mass and concomitant reduction in contractile strength plays a central role in frailty syndrome. Age-related neuronal impairments are closely associated with sarcopenia in the elderly, which is characterized by severe muscular atrophy that can considerably lessen the [...] Read more.

The progressive loss of skeletal muscle mass and concomitant reduction in contractile strength plays a central role in frailty syndrome. Age-related neuronal impairments are closely associated with sarcopenia in the elderly, which is characterized by severe muscular atrophy that can considerably lessen the overall quality of life at old age. Mass-spectrometry-based proteomic surveys of senescent human skeletal muscles, as well as animal models of sarcopenia, have decisively improved our understanding of the molecular and cellular consequences of muscular atrophy and associated fiber-type shifting during aging. This review outlines the mass spectrometric identification of proteome-wide changes in atrophying skeletal muscles, with a focus on contractile proteins as potential markers of changes in fiber-type distribution patterns. The observed trend of fast-to-slow transitions in individual human skeletal muscles during the aging process is most likely linked to a preferential susceptibility of fast-twitching muscle fibers to muscular atrophy. Studies with senescent animal models, including mostly aged rodent skeletal muscles, have confirmed fiber-type shifting. The proteomic analysis of fast versus slow isoforms of key contractile proteins, such as myosin heavy chains, myosin light chains, actins, troponins and tropomyosins, suggests them as suitable bioanalytical tools of fiber-type transitions during aging. Full article

(This article belongs to the Special Issue Muscle Atrophy: From Bench to Bedside)

► Show Figures

Figure 1

10 pages, 918 KiB

Open AccessReview

The Role of Skeletal Muscle Mitochondria in Colorectal Cancer Related Cachexia: Friends or Foes?

by Britt van de Haterd, Kenneth Verboven, Frank Vandenabeele and Anouk Agten

Int. J. Mol. Sci. 2022, 23(23), 14833; https://doi.org/10.3390/ijms232314833 - 27 Nov 2022

Cited by 1 | Viewed by 1867

Abstract

Up to 60% of colorectal cancer (CRC) patients develop cachexia. The presence of CRC related cachexia is associated with more adverse events during systemic therapy, leading to a high mortality rate. The main manifestation in CRC related cachexia is the loss of skeletal [...] Read more.

Up to 60% of colorectal cancer (CRC) patients develop cachexia. The presence of CRC related cachexia is associated with more adverse events during systemic therapy, leading to a high mortality rate. The main manifestation in CRC related cachexia is the loss of skeletal muscle mass, resulting from an imbalance between skeletal muscle protein synthesis and protein degradation. In CRC related cachexia, systemic inflammation, oxidative stress, and proteolytic systems lead to mitochondrial dysfunction, resulting in an imbalanced skeletal muscle metabolism. Mitochondria fulfill an important function in muscle maintenance. Thus, preservation of the skeletal muscle mitochondrial homeostasis may contribute to prevent the loss of muscle mass. However, it remains elusive whether mitochondria play a benign or malignant role in the development of cancer cachexia. This review summarizes current (mostly preclinical) evidence about the role of skeletal muscle mitochondria in the development of CRC related cachexia. Future human research is necessary to determine the physiological role of skeletal muscle mitochondria in the development of human CRC related cachexia. Full article

(This article belongs to the Special Issue Muscle Atrophy: From Bench to Bedside)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Muscle Atrophy: From Bench to Bedside

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Published Papers (8 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI