Forkhead Box O Signaling Pathway in Skeletal Muscle Atrophy
2022; Elsevier BV; Volume: 192; Issue: 12 Linguagem: Inglês
10.1016/j.ajpath.2022.09.003
ISSN1525-2191
AutoresKun Chen, Peng Gao, Zongchao Li, Aonan Dai, Ming Yang, Siyu Chen, Jingyue Su, Zhenhan Deng, Liangjun Li,
Tópico(s)Signaling Pathways in Disease
ResumoSkeletal muscle atrophy is the consequence of protein degradation exceeding protein synthesis because of disease, aging, and physical inactivity. Patients with skeletal muscle atrophy have decreased muscle mass and fiber cross-sectional area, and experience reduced survival quality and motor function. The forkhead box O (FOXO) signaling pathway plays an important role in the pathogenesis of skeletal muscle atrophy by regulating E3 ubiquitin ligases and some autophagy factors. However, the mechanism of FOXO signaling pathway leading to skeletal muscle atrophy is still unclear. The development of treatment strategies for skeletal muscle atrophy has been a thorny clinical problem. FOXO-targeted therapy to treat skeletal muscle atrophy is a promising approach, and an increasing number of relevant studies have been reported. This article reviews the mechanism and therapeutic targets of the FOXO signaling pathway mediating skeletal muscle atrophy, and provides ideas for the clinical treatment of this condition. Skeletal muscle atrophy is the consequence of protein degradation exceeding protein synthesis because of disease, aging, and physical inactivity. Patients with skeletal muscle atrophy have decreased muscle mass and fiber cross-sectional area, and experience reduced survival quality and motor function. The forkhead box O (FOXO) signaling pathway plays an important role in the pathogenesis of skeletal muscle atrophy by regulating E3 ubiquitin ligases and some autophagy factors. However, the mechanism of FOXO signaling pathway leading to skeletal muscle atrophy is still unclear. The development of treatment strategies for skeletal muscle atrophy has been a thorny clinical problem. FOXO-targeted therapy to treat skeletal muscle atrophy is a promising approach, and an increasing number of relevant studies have been reported. This article reviews the mechanism and therapeutic targets of the FOXO signaling pathway mediating skeletal muscle atrophy, and provides ideas for the clinical treatment of this condition. Skeletal muscle is the most abundant tissue in the human body, accounting for 40% to 50% of the total mass of a healthy individual.1Sartori R. Romanello V. Sandri M. Mechanisms of muscle atrophy and hypertrophy: implications in health and disease.Nat Commun. 2021; 12: 330Crossref PubMed Scopus (138) Google Scholar It not only controls movement, but also participates in multiple life activities, including breathing, eating, energy consumption, and nutrient metabolism.1Sartori R. Romanello V. Sandri M. Mechanisms of muscle atrophy and hypertrophy: implications in health and disease.Nat Commun. 2021; 12: 330Crossref PubMed Scopus (138) Google Scholar The loss of skeletal muscle volume and mass because of inactivity, disease, and aging is known as skeletal muscle atrophy, and is characterized by decreased muscle fiber cross-sectional area and muscle protein content.1Sartori R. Romanello V. Sandri M. Mechanisms of muscle atrophy and hypertrophy: implications in health and disease.Nat Commun. 2021; 12: 330Crossref PubMed Scopus (138) Google Scholar, 2Kandarian S.C. Jackman R.W. Intracellular signaling during skeletal muscle atrophy.Muscle Nerve. 2006; 33: 155-165Crossref PubMed Scopus (282) Google Scholar, 3Miller S.G. Hafen P.S. Brault J.J. Increased adenine nucleotide degradation in skeletal muscle atrophy.Int J Mol Sci. 2020; 21: 88Crossref Scopus (18) Google Scholar Skeletal muscle atrophy may cause reduction in muscle function and quality of life.3Miller S.G. Hafen P.S. Brault J.J. Increased adenine nucleotide degradation in skeletal muscle atrophy.Int J Mol Sci. 2020; 21: 88Crossref Scopus (18) Google Scholar There are many diseases that can cause skeletal muscle atrophy, such as diabetes and cachexia, which can significantly affect the prognosis of patients and increase mortality.4Reed S.A. Sandesara P.B. Senf S.M. Judge A.R. Inhibition of FoxO transcriptional activity prevents muscle fiber atrophy during cachexia and induces hypertrophy.FASEB J. 2011; 26: 987-1000Crossref PubMed Scopus (0) Google Scholar,5O'Neill B.T. Bhardwaj G. Penniman C.M. Krumpoch M.T. Suarez Beltran P.A. Klaus K. Poro K. Li M. Pan H. Dreyfuss J.M. Nair K.S. Kahn C.R. FoxO transcription factors are critical regulators of diabetes-related muscle atrophy.Diabetes. 2019; 68: 556-570Crossref PubMed Scopus (68) Google Scholar Skeletal muscle atrophy itself is not life threatening, but its complications (such as osteoporosis, blood clots, and pressure sores) can lead to morbidity and mortality.6Cao R.Y. Li J. Dai Q. Li Q. Yang J. Muscle atrophy: present and future.Adv Exp Med Biol. 2018; 1088: 605-624Crossref PubMed Scopus (12) Google Scholar Skeletal muscle atrophy is common in clinical practice, but its treatment strategies are largely limited to traditional methods, such as physical exercise and nutritional supplementation, with no effective treatment.7Yin L. Li N. Jia W. Wang N. Liang M. Yang X. Du G. Skeletal muscle atrophy: from mechanisms to treatments.Pharmacol Res. 2021; 172: 105807Crossref PubMed Scopus (13) Google Scholar Therefore, it is imperative to find new targets or drugs to treat skeletal muscle atrophy. The insulin-like growth factor-1/phosphatidylinositol-3-hydroxykinase/V-akt murine thymoma viral oncogene homolog (IGF-1/PI3K/AKT) signaling pathway, which can be activated by cellular stimulation or toxic injury, regulates essential cellular functions such as transcription, translation, proliferation, growth, and survival. Besides the aforementioned functions, the IGF-1/PI3K/AKT signaling pathway regulates the gain and loss of skeletal muscle mass.8Léger B. Cartoni R. Praz M. Lamon S. Dériaz O. Crettenand A. Gobelet C. Rohmer P. Konzelmann M. Luthi F. Russell A.P. Akt signalling through GSK-3beta, mTOR and Foxo1 is involved in human skeletal muscle hypertrophy and atrophy.J Physiol. 2006; 576: 923-933Crossref PubMed Scopus (0) Google Scholar Activation of AKT can affect key cellular processes by phosphorylating the substrates involved in apoptosis, protein synthesis, metabolism, and cell cycle.9Timmer L.T. Hoogaars W.M.H. Jaspers R.T. 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Lee E. Sohn U.D. Kim I. Forkhead box O3 plays a role in skeletal muscle atrophy through expression of e3 ubiquitin ligases MuRF-1 and atrogin-1 in Cushing's syndrome.Am J Physiol Endoc M. 2017; 312: E495-E507Crossref PubMed Scopus (0) Google Scholar,15Oyabu M. Takigawa K. Mizutani S. Hatazawa Y. Fujita M. Ohira Y. Sugimoto T. Suzuki O. Tsuchiya K. Suganami T. Ogawa Y. Ishihara K. Miura S. Kamei Y. FOXO1 cooperates with C/EBPδ and ATF4 to regulate skeletal muscle atrophy transcriptional program during fasting.FASEB J. 2022; 36: e22152Crossref PubMed Scopus (3) Google Scholar By summarizing the regulatory role of FOXO signaling pathway in the pathogenesis of skeletal muscle atrophy and the possible therapeutic strategies to treat skeletal muscle atrophy through the FOXO signaling pathway, this article aims to provide ideas for future clinical treatment. Skeletal muscle atrophy types include primary muscle atrophy and secondary muscle atrophy.7Yin L. Li N. Jia W. Wang N. Liang M. Yang X. Du G. Skeletal muscle atrophy: from mechanisms to treatments.Pharmacol Res. 2021; 172: 105807Crossref PubMed Scopus (13) Google Scholar Primary muscle atrophy includes muscular dystrophy, congenital myopathy, mitochondrial myopathy, and metabolic myopathy,7Yin L. Li N. Jia W. Wang N. Liang M. Yang X. Du G. Skeletal muscle atrophy: from mechanisms to treatments.Pharmacol Res. 2021; 172: 105807Crossref PubMed Scopus (13) Google Scholar whereas pathologic conditions leading to secondary muscle atrophy include neuromuscular diseases, cancer, chronic inflammatory diseases, and acute critical illness.7Yin L. Li N. Jia W. Wang N. Liang M. Yang X. Du G. Skeletal muscle atrophy: from mechanisms to treatments.Pharmacol Res. 2021; 172: 105807Crossref PubMed Scopus (13) Google Scholar,16Powers S. Lynch G.S. Murphy K.T. Reid M.B. Zijdewind I. Disease-induced skeletal muscle atrophy and fatigue.Med Sci Sports Exerc. 2016; 48: 2307-2319Crossref PubMed Scopus (85) Google Scholar Regardless of the pathogenesis, the stability of skeletal muscle mass is the result of the balance between protein anabolism and catabolism, covering both direct and indirect regulation of multiple factors.17Wang Y. Pessin J.E. Mechanisms for fiber-type specificity of skeletal muscle atrophy.Curr Opin Clin Nutr. 2013; 16: 243-250Crossref PubMed Scopus (0) Google Scholar,18Wilburn D. Ismaeel A. Machek S. Fletcher E. Koutakis P. Shared and distinct mechanisms of skeletal muscle atrophy: a narrative review.Ageing Res Rev. 2021; 71: 101463Crossref PubMed Scopus (3) Google Scholar Muscle anabolism is driven by growth hormone, insulin, IGF-1, and testosterone, and muscle catabolism is regulated by endocrine, inflammatory, and oxidative stress factors.19Malavaki C.J. Sakkas G.K. Mitrou G.I. Kalyva A. Stefanidis I. Myburgh K.H. Karatzaferi C. Skeletal muscle atrophy: disease-induced mechanisms may mask disuse atrophy.J Muscle Res Cell M. 2016; 36: 405-421Crossref Scopus (32) Google Scholar Four proteolytic systems are known to be involved in muscle atrophy [namely, the ubiquitin proteasome system (UPS), the autophagy lysosome system, the cysteine aspartic proteases, and the calpain system].1Sartori R. Romanello V. Sandri M. Mechanisms of muscle atrophy and hypertrophy: implications in health and disease.Nat Commun. 2021; 12: 330Crossref PubMed Scopus (138) Google Scholar,7Yin L. Li N. Jia W. Wang N. Liang M. Yang X. Du G. Skeletal muscle atrophy: from mechanisms to treatments.Pharmacol Res. 2021; 172: 105807Crossref PubMed Scopus (13) Google Scholar The FOXO signaling pathway is primarily related to the UPS and the autophagy lysosome system. Different types of FOXOs can regulate multiple genes in UPS and autophagy. UPS is composed of ubiquitin activase, ubiquitin-binding enzyme, ubiquitin protein ligase (E3), ubiquitin, and 26S proteasome.20Park J. Cho J. Song E.J. Ubiquitin–proteasome system (UPS) as a target for anticancer treatment.Arch Pharm Res. 2020; 43: 1144-1161Crossref PubMed Scopus (2) Google Scholar Among these, the ubiquitin E3 ligase muscle ring finger 1 (MuRF-1) and F-box (MAFbx)/Atrogin-1, a ligase that ubiquitinates desmin muscle atrophy, are downstream regulatory genes of the FOXO signaling pathway. MuRF-1 is the most significant UPS factor in skeletal muscle atrophy and plays a role in myofibril degradation. Atrogin-1 is also involved in skeletal muscle atrophy.7Yin L. Li N. Jia W. Wang N. Liang M. Yang X. Du G. Skeletal muscle atrophy: from mechanisms to treatments.Pharmacol Res. 2021; 172: 105807Crossref PubMed Scopus (13) Google Scholar Ubiquitin forms compounds with ubiquitin activase and ubiquitin-binding enzyme in sequence, and transfers the protein to E3 for processing, where the protein is finally degraded in the 26S proteasome, leading to peptide degradation and ubiquitin release for recycling.7Yin L. Li N. Jia W. Wang N. Liang M. Yang X. Du G. Skeletal muscle atrophy: from mechanisms to treatments.Pharmacol Res. 2021; 172: 105807Crossref PubMed Scopus (13) Google Scholar FOXO3 regulates essential autophagy genes in the autophagy lysosome system, including Bnip3, Gabarap, LC3, and Atg12.21Rocchi A. He C. Regulation of exercise-induced autophagy in skeletal muscle.Curr Pathobiol Rep. 2017; 5: 177-186Crossref PubMed Scopus (25) Google Scholar The IGF-1/PI3K/AKT signaling pathway plays an important role in skeletal muscle mass homeostasis.22Sartorelli V. Fulco M. 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Molecular and cellular determinants of skeletal muscle atrophy and hypertrophy.Science's STKE. 2004; 2004: re11Crossref PubMed Scopus (0) Google Scholar,24Sandri M. Signaling in muscle atrophy and hypertrophy.Physiology. 2008; 23: 160-170Crossref PubMed Scopus (606) Google Scholar mTOR kinase interacts with several proteins to form two complexes: rapamycin-sensitive mTOR complex 1 (mTORC1) containing Raptor, and rapamycin-insensitive mTORC2 containing Rictor.1Sartori R. Romanello V. Sandri M. Mechanisms of muscle atrophy and hypertrophy: implications in health and disease.Nat Commun. 2021; 12: 330Crossref PubMed Scopus (138) Google Scholar,24Sandri M. Signaling in muscle atrophy and hypertrophy.Physiology. 2008; 23: 160-170Crossref PubMed Scopus (606) Google Scholar mTORC1 is mainly involved in protein synthesis. Phosphorylation of mTORC1 is mediated by the Raptor-interacting protein to inhibit the eukaryotic cell initiation factor 4E binding protein 1 (4EBP1). The mTORC1-mediated inhibition of 4EBP1 further leads to the activation of the eukaryotic cell initiation factor 4E, thereby increasing protein synthesis.3Miller S.G. Hafen P.S. Brault J.J. Increased adenine nucleotide degradation in skeletal muscle atrophy.Int J Mol Sci. 2020; 21: 88Crossref Scopus (18) Google Scholar,22Sartorelli V. Fulco M. Molecular and cellular determinants of skeletal muscle atrophy and hypertrophy.Science's STKE. 2004; 2004: re11Crossref PubMed Scopus (0) Google Scholar mTORC1 can also lead to increased protein synthesis through phosphorylation and activation of the p70 ribosomal protein S6 kinase.3Miller S.G. Hafen P.S. Brault J.J. Increased adenine nucleotide degradation in skeletal muscle atrophy.Int J Mol Sci. 2020; 21: 88Crossref Scopus (18) Google Scholar,24Sandri M. Signaling in muscle atrophy and hypertrophy.Physiology. 2008; 23: 160-170Crossref PubMed Scopus (606) Google Scholar The detailed mechanism is shown in Figure 1. FOXOs are one of the major targets of the IGF-1/PI3K/AKT signaling pathway.25Zhang X. Tang N. Hadden T.J. Rishi A.K. Akt, FoxO and regulation of apoptosis.Biochim Biophys Acta. 2011; 1813: 1978-1986Crossref PubMed Scopus (713) Google Scholar The first gene containing the forkhead region was discovered in 1989 by Weigel et al26Weigel D. Jürgens G. Küttner F. Seifert E. Jäckle H. The homeotic gene fork head encodes a nuclear protein and is expressed in the terminal regions of the Drosophila embryo.Cell. 1989; 57: 645-658Abstract Full Text PDF PubMed Scopus (608) Google Scholar while studying Drosophila. FOXOs are the evolutionarily conserved transcription factors of metabolic and stress responses, responsible for regulating the genes associated with autophagy, oxidative stress, energy metabolism, and muscle atrophy.12Monsalve M. Olmos Y. The complex biology of FOXO.Curr Drug Targets. 2011; 12: 1322-1350Crossref PubMed Scopus (94) Google Scholar,27Bhardwaj G. Penniman C.M. Jena J. 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The FoxO code.Oncogene. 2008; 27: 2276-2288Crossref PubMed Scopus (901) Google Scholar The regulation of FOXOs through these stimuli is achieved by alterations in the posttranslational modifications of FOXOs, including phosphorylation, acetylation, and ubiquitination modifications.29Link W. Introduction to FOXO biology.Methods Mol Biol. 2019; 1890: 1-9Crossref PubMed Scopus (70) Google Scholar Phosphorylation is the predominant posttranslational modification regulating the FOXO activity and can be mediated by several kinases, including AKT, AMP-activated protein kinase, c-Jun N-terminal kinase, protein arginine methyltransferase, serum- and glucocorticoid-inducible kinase, extracellular signal-regulated kinase, p38, cyclin-dependent kinase 2, casein kinase 1, and mammalian STE20-like protein kinase 1, each recognizing a specific sequence in the FOXO.13Calissi G. Lam E.W. Link W. Therapeutic strategies targeting FOXO transcription factors.Nat Rev Drug Discovery. 2021; 20: 21-38Crossref PubMed Scopus (0) Google Scholar The most particular input to FOXO activity is the AKT activation signal in the presence of growth factors.29Link W. Introduction to FOXO biology.Methods Mol Biol. 2019; 1890: 1-9Crossref PubMed Scopus (70) Google Scholar Phosphorylation of FOXOs by the IGF-1/PI3K/AKT signaling pathway leads to their translocation to the cytoplasm and subsequent inactivation.30Cheng Z. The FoxO–autophagy axis in health and disease.Trends Endocrinol Metab. 2019; 30: 658-671Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,31Farhan M. Wang H. Gaur U. Little P.J. Xu J. Zheng W. 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They concluded that, in the normally growing skeletal muscle, the upstream AKT suppresses the FOXO-mediated expression of ubiquitin ligase Atrogin-1, thereby inhibiting skeletal muscle atrophy.43Sandri M. Sandri C. Gilbert A. Skurk C. Calabria E. Picard A. Walsh K. Schiaffino S. Lecker S.H. Goldberg A.L. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy.Cell. 2004; 117: 399-412Abstract Full Text Full Text PDF PubMed Scopus (2174) Google Scholar The specific mechanism of the action of AKT was attributed to the phosphorylation of FOXOs, which are transferred to the cytoplasm and inactivated.16Powers S. Lynch G.S. Murphy K.T. Reid M.B. Zijdewind I. Disease-induced skeletal muscle atrophy and fatigue.Med Sci Sports Exerc. 2016; 48: 2307-2319Crossref PubMed Scopus (85) Google Scholar Kang et al14Kang S. Lee H. Kim M. Lee E. Sohn U.D. Kim I. Forkhead box O3 plays a role in skeletal muscle atrophy through expression of e3 ubiquitin ligases MuRF-1 and atrogin-1 in Cushing's syndrome.Am J Physiol Endoc M. 2017; 312: E495-E507Crossref PubMed Scopus (0) Google Scholar proposed a mechanism by which the glucocorticoid receptor and FOXO3 act as regulators of muscle atrophy in a rat model of Cushing syndrome. The authors further pointed out that FOXO3 is involved in muscle atrophy by regulating MuRF-1 and Atrogin-1.14Kang S. Lee H. Kim M. Lee E. Sohn U.D. Kim I. Forkhead box O3 plays a role in skeletal muscle atrophy through expression of e3 ubiquitin ligases MuRF-1 and atrogin-1 in Cushing's syndrome.Am J Physiol Endoc M. 2017; 312: E495-E507Crossref PubMed Scopus (0) Google Scholar A new group of novel ubiquitin ligases regulated by FOXO, MUSA1, SMART, FBXO31, and Itch, were identified in recent studies and were shown to be closely associated with skeletal muscle atrophy.44Brocca L. Toniolo L. Reggiani C. Bottinelli R. Sandri M. 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