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Hypoxia and Hypoxia-Inducible Factor Signaling in Muscular Dystrophies: Cause and Consequences

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Hypoxia and Hypoxia-Inducible Factor Signaling in Muscular Dystrophies: Cause and Consequences International Journal of Molecular Sciences Review Hypoxia and Hypoxia-Inducible Factor Signaling in Muscular Dystrophies: Cause and Consequences Thuy-Hang Nguyen 1, Stephanie Conotte 1, Alexandra Belayew 1 , Anne-Emilie Declèves 2 , Alexandre Legrand 1 and Alexandra Tassin 1,* 1 Laboratory of Respiratory Physiology, Pathophysiology and Rehabilitation, Research Institute for Health Sciences and Technology, University of Mons, 7000 Mons, Belgium; [email protected] (T.-H.N.); [email protected] (S.C.); [email protected] (A.B.); [email protected] (A.L.) 2 Department of Metabolic and Molecular Biochemistry, Research Institute for Health Sciences and Technology, University of Mons, 7000 Mons, Belgium; [email protected] * Correspondence: [email protected] Abstract: Muscular dystrophies (MDs) are a group of inherited degenerative muscle disorders characterized by a progressive skeletal muscle wasting. Respiratory impairments and subsequent hypoxemia are encountered in a significant subgroup of patients in almost all MD forms. In response to hypoxic stress, compensatory mechanisms are activated especially through Hypoxia-Inducible Factor 1 α (HIF-1α). In healthy muscle, hypoxia and HIF-1α activation are known to affect oxidative stress balance and metabolism. Recent evidence has also highlighted HIF-1α as a regulator of myogenesis and satellite cell function. However, the impact of HIF-1α pathway modifications in MDs remains to be investigated. Multifactorial pathological mechanisms could lead to HIF-1α activation in patient skeletal muscles. In addition to the genetic defect per se, respiratory failure or blood vessel Citation: Nguyen, T.-H.; Conotte, S.; alterations could modify hypoxia response pathways. Here, we will discuss the current knowledge Belayew, A.; Declèves, A.-E.; Legrand, A.; Tassin, A. Hypoxia and about the hypoxia response pathway alterations in MDs and address whether such changes could Hypoxia-Inducible Factor Signaling influence MD pathophysiology. in Muscular Dystrophies: Cause and Consequences. Int. J. Mol. Sci. 2021, Keywords: hypoxia; myopathies; HIF-1α 22, 7220. https://doi.org/10.3390/ ijms22137220 Academic Editor: Jung-Ae Kim 1. Introduction Muscular dystrophies (MDs) are a heterogeneous group of inherited degenerative Received: 31 May 2021 muscle disorders resulting in progressive muscle weakness and dystrophic histopathology Accepted: 30 June 2021 observed on muscle biopsies. Clinically, MDs are characterized by a high variability in Published: 5 July 2021 terms of age of onset, severity, and progression. MDs are also very heterogeneous in their genetic features and the distribution of the affected muscles, including or not an impact Publisher’s Note: MDPI stays neutral on cardiac or respiratory muscles as well as extra-muscular manifestations such as insulin with regard to jurisdictional claims in resistance. published maps and institutional affil- Respiratory impairments are frequent MD clinical manifestations and associated to iations. hypoxemia in subgroups of patients [1–3]. At the tissue level, hypoxemia leads to cellular hypoxia. In primary muscle disorders, the impact of hypoxia on muscle pathophysiology remains poorly documented [4]. This is particularly surprising since several MDs are known to cause chronic hypoxemia due to hypoventilation as a consequence of respiratory Copyright: © 2021 by the authors. muscle weakness. Licensee MDPI, Basel, Switzerland. The Nobel prize in Physiology or Medicine was awarded in 2019 to William G. Kaelin This article is an open access article Jr, Peter J. Ratcliffe and Gregg L. Semenza “for their discoveries of how cells sense and distributed under the terms and adapt to oxygen availability” [5]. They uncovered the main effectors of the hypoxic conditions of the Creative Commons response, the HIF transcription factor family, and how oxygen-dependent post-translational Attribution (CC BY) license (https:// α creativecommons.org/licenses/by/ modifications of HIF-1/2 lead to their degradation in normoxic conditions and their 4.0/). activation in hypoxia. HIF factors (HIF-1, HIF-2, HIF-3) are heterodimers composed of an Int. J. Mol. Sci. 2021, 22, 7220. https://doi.org/10.3390/ijms22137220 https://www.mdpi.com/journal/ijms Int. J. Mol.Int. Sci. J.2021 Mol. ,Sci.22, 2021 7220, 21, x FOR PEER REVIEW 2 of 342 of 33 oxygen-regulated α subunit and a stable β subunit. HIF-1α and HIF-2α are considered as modifications of HIF-1/2 α lead to their degradation in normoxic conditions and their ac- the mastertivation regulators in hypoxia. of HIF the factors hypoxic (HIF-1, response HIF-2, transcriptional HIF-3) are heterodimers program. composed Under normoxic of an conditions,oxygen-regulated HIFα subunits α subunit are and constantly a stable β expressed subunit. HIF-1 butα rapidly and HIF-2 degradedα are considered by a complex as mechanism.the master They regulators are first of hydroxylated the hypoxic respon by specificse transcriptional Prolyl Hydroxylase program. Domain-containingUnder normoxic enzymesconditions, (PHD). HIF Thisα subunits reaction are is oxygen-dependent,constantly expressed sincebut rapidly the transferred degraded by hydroxyl a complex group is derivedmechanism. from They the Oare2 firstmolecule. hydroxylated This reactionby specific also Prolyl requires Hydroxylase three Domain-contain- cofactors, namely 2-oxoglutarate,ing enzymes vitamin (PHD). C, This and reaction iron [6 ].is Then,oxygen the-dependent, Von Hippel–Lindau since the transferred (pVHL) E3hydroxyl ubiquitin- ligasegroup recognizes is derived hydroxylated from the O2 molecule. HIFα forms This andreaction activates also requires their ubiquitination three cofactors, namely leading to their2-oxoglutarate, degradation by vitamin the proteasome. C, and iron [6]. By Th contrast,en, the Von under Hippel–Lindau hypoxic conditions, (pVHL) E3 PHD ubiqui- cannot tin-ligase recognizes hydroxylated HIFα forms and activates their ubiquitination leading hydroxylate HIFα because of the decreased O2 availability, allowing for HIFα stabilization, dimerizationto their degradation with HIF1 byβ, the and proteasome. translocation By contrast, into the under nucleus. hypoxic HIF conditions, factors then PHD activatecan- not hydroxylate HIFα because of the decreased O2 availability, allowing for HIFα stabili- the transcription of more than a hundred target genes through their binding to a specific zation, dimerization with HIF1β, and translocation into the nucleus. HIF factors then ac- DNAtivate sequence the transcription called Hypoxia of more Response than a hund Elementred target (HRE) genes [7 through–10] (Figure their 1binding and Table to a 1). HIF-1specificα and DNA HIF-2 sequenceα belong called to the Hypoxia basic helix-loop-helixResponse Element (bHLH)(HRE) [7– family10] (Figure of transcription 1 and Ta- factorsble and 1). HIF-1 exhibitα and a highly HIF-2α conserved belong to the structure basic helix-loop-helix and functional (bHLH) similarities. family of However,transcrip- an increasingtion factors number and ofexhibit studies a highly point conserved to differences structure in transcriptional and functional similarities. regulation However, and function in responsean increasing to hypoxia number and of instudies disease point states to differences [11]. The rolein transcriptional of HIF-3 is stillregulation debated and since its genefunction can express in response multiple to hypoxia variants and in exhibiting disease states different [11]. The activities, role of HIF-3 some is still of which debated were reportedsince as its negative gene can regulatorsexpress multiple of HIF-1/2 variantsα [ex12hibiting]. different activities, some of which were reported as negative regulators of HIF-1/2α [12]. Figure 1. Regulation of HIF pathway. Under normoxia, HIFα protein is hydroxylated by PHDs and Figuresubsequently 1. Regulation recognized of by HIF pVHL pathway. and degraded Under through normoxia, the ubiquitin–proteasome HIFα protein is hydroxylated pathway. In byhypoxia, PHDs PHD and activity subsequently is inhibited recognized by the decreased by pVHL O2 levels and degradedand thus HIF throughα hydroxylation. the ubiquitin– HIFα is proteasome pathway. In hypoxia, PHD activity is inhibited by the decreased O2 levels and thus HIFα hydroxylation. HIFα is therefore stabilized and translocated into the nucleus, dimerizes with HIF1β, and activates the expression of hypoxia responsive genes with additional transcriptional co-factors, such as CBP/P300. Ub = ubiquitin. Int. J. Mol. Sci. 2021, 22, 7220 3 of 33 Table 1. Main HIF-1α target genes and regulated pathways. Regulated Pathways HIF-1α Target Genes VEGF and VEGF receptor FLT1, Angiogenesis and erythropoiesis heme oxygenase 1, NOS 2 and 3, PDGF ALDA, ALDOC, ENO1, GAPDH, HK1, HK2, Metabolism LDH A, PFKL, PGK1, PKM, and TPI GLUT-1, 3, 4, PDK1 Proliferation and survival Cyclin G2, TGFα and β3, IGF-2 Apoptosis BNIP3/3L, P53 Myogenesis WNT signaling Compared to other oxygen-sensitive tissues such as the brain and heart, skeletal muscles tolerate hypoxia quite well because of their plasticity. Indeed, they adapt their metabolism and structural features (fiber size, muscle fiber type, mitochondrial activity, myoglobin content) as well as blood supply (capillary density) in response to hypoxia, a condition muscles encounter in non-pathological contexts e.g., physical exercise or exposure to high altitude [13–15]. Obviously, muscle adaptation will strongly depend on exercise training
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