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Funding Information: Research in the authors\u2019 laboratories is funded as follows: AIR and AC by the Spanish Ministry of Science, Innovation and Universities (PID2019-110061RB-I00, PID-2021-122766OB-100, PDC2021-121421-I00, PDC2022-133765-I00), CIBERNED/ISCIII (CB06/05/0010), and The Autonomous Community of Madrid (P2022/BMD-7230). MGL is funded by Spanish Ministry of Science, Innovation and Universities (PID2021-125986OB-I00, PDC2022-133809-I00) and Community of Madrid Ref. P2022/BMD-7230-CAM-22. PR is funded by Spanish Ministry of Science, Innovation and Universities (PID2023-150994OB-I00), The Autonomous Community of Madrid (P2022/BMD-7227) and CIBERDEM/ISCIII (CB07/08/0033). JJV is holder of a FPU contract of Spanish Ministry of Science, Innovation and Universities (FPU20/03326). ILB is funded by the Spanish Ministry of Science, Innovation and Universities (PID2022-137065OB-100, PCD2022-133774-100) and CIBERNED/ISCIII (CB06/05/0089). MCS, ST and ASF are funded by Funda\u00E7\u00E3o para a Ci\u00EAncia e a Tecnologia through R&D unit iNOVA4Health (UIDB/04462/2020 and UIDP/04462/2020) and LS4FUTURE Associated Laboratory (LA/P/0087/2020). ASF is holder of a post-doctoral contract from \u201CLa Caixa Foundation\u201D (NASCENT HR22-00569). IM received research core funding by Slovenian Research Agency (P3-0019). AG received research funding from the National Science Centre grant OPUS (2021/43/B/NZ4/02130). ARC is supported by the donor Henrique Meirelles who chose to support the MATRIHEALTH Project (CC1036), Funda\u00E7\u00E3o para a Ci\u00EAncia e a Tecnologia Project (http://dx.doi.org/10.54499/PTDC/BTM-ORG/1383/2020) and Unit Funding (http://dx.doi.org/10.54499/UIDB/00329/2020). IPT acknowledges funding from NKUA SARG (C.S. 19067). SC is funded by the ISCIII (PI23/01846). LVM is a grant holder of a contract \u041A\u041F-06-\u041A\u041E\u0421\u0422/4 of the Bulgarian National Science Fund under BG-175467353-2023-03 programme. LVM and MIG have received funding from the European Union\u2019s Horizon 2020 research and innovation programme, project PlantaSYST (SGA No 739582 under FPA No. 664620) and by the European Regional Development Fund through the Bulgarian \u201CScience and Education for Smart Growth\u201D Operational Programme (BG05M2OP001-1.003-001-C01) and Programme Research Innovation and Digitalisation for Smart Transformation. OK is funded by the European Union Horizon's research and innovation program HORIZON-HLTH-2022-STAYHLTH-02 under agreement No 101095679. ADK is funded by the Medical Research Council UK (MR/W023806/1), the Biotechnology and Biological Sciences Research Council UK (BB/T508111/1 and BB/X00029X/1), Tenovus Scotland (T22-08), and the Cunnigham Trust. This article is based upon work from COST Action CA20121, supported by COST (European Cooperation in Science and Technology) ( www.cost.eu ) ( https://benbedphar.org/about-benbedphar/ ). Funding Information: In skeletal muscles, ROS management is particularly relevant. The levels of ROS fluctuate in line with the intensity of muscle contraction, which is directly linked to mitochondrial activity, and mediate a series of physiological adaptations. Apart from the superoxide anions generated by the mitochondria, labile iron is also an important element in oxidative stress signaling in the muscle, with approximately 10\u201315 % of total iron or heme-iron of the body found in skeletal muscle. The importance of heme-iron in the correct functioning of the skeletal muscle is further illustrated by the fact that heme is a co-factor of key cellular components, including myoglobin and cytochrome c oxidase. Under pathological conditions, ROS accumulation in the muscle leads to mitochondrial dysfunction and muscle atrophy, a common feature in several muscular dystrophies, a group of diseases characterized by progressive weakness and loss of muscle mass [270\u2013273]. Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy diagnosed during childhood and is characterized by mutations in DMD, which encodes the cytoskeleton-transmembrane receptor bridging protein, dystrophin [274]. As for other muscular dystrophies, increased oxidative stress [275,276], iron overload [277], as well as chronic inflammation [278,279] are hallmarks of DMD and therefore antioxidant mechanisms led by NRF2, have been the focus of intense research [280,281]. These studies have shed light on the importance of NRF2 and downstream targets to counter the oxidative stress linked to muscular dystrophies (Table 8). In particular, the crosstalk between increased ROS and inflammatory response has been shown to occur both in patients and in mdx mice [281], the preferred mouse model for DMD. This crosstalk is likely mediated by NF-\u03BAB activation in response to mechanical stress and related production of ROS, as shown in previous studies using the mdx mouse model [282]. In accordance, NRF2 induction dampens NF-\u03BAB activation, consequently reducing the inflammatory response [283]. Further supporting a direct role of NRF2 in countering disease pathology in the context of muscular dystrophies, deletion of Nrf2 in the natural A/J mouse model of dysferlinopathy, associated with mutations in DYSF, led to a dramatic increase in disease pathology [284]. NRF2 has also been shown to play a role in skeletal muscle regeneration. Absence of NRF2 in a model of hindlimb ischemia-reperfusion injury (i.e. muscle injury), did not worsen the extent of the injury, but led to an impairment in muscle regeneration, which is likely associated with the transcriptional modulation of key myogenic factors and consequently to the regulation of muscle stem cell proliferation and differentiation [285]. The role of NRF2 in skeletal muscle physiology has also been tested in the context of exercise, where Keap1 knockdown mice (Keap1-KD) had increased exercise endurance [286]. Moreover, different studies have also shown that Nfe2l2 deletion worsens the muscle ageing phenotype [287\u2013289]. Together these findings support the idea that inducing antioxidant mechanisms may be the key to counter the overall disease pathology in muscular dystrophies. In keeping with this notion, several studies have tested the ability of classic antioxidant compounds, such as NAC to revert disease pathology in mdx mice [290\u2013292]. In addition to DMD, treatment with NAC has also been used to evaluate the effectiveness of antioxidant treatment in countering other types of muscular dystrophies. This is true for LAMA2 congenital muscular dystrophy (LAMA2-CMD), a disease caused by mutations in LAMA2, encoding the \u03B12 chain of laminins 211 and 221 [272,293]. NAC treatment was shown to counter muscle weakness, prevent the erroneous central nucleation of muscle fibers and decrease apoptosis, inflammation, fibrosis and oxidative stress [293]. NAC treatment was also shown to allow muscle regeneration upon injury in Stra13\u2212/\u2212 mice, which lack the basic helix-loop-helix transcription factor Stra13 (or Bhlhe40), known to play an important role in muscle development [294]. Contrasting with this beneficial role of NAC in the treatment of muscular dystrophies, some studies have also highlighted NAC side effects, including a negative impact on body weight gain and gain of muscle mass and a decrease in the liver weight [291,295] thus supporting the use of other strategies based on the activation of endogenous mechanisms. Nevertheless, and considering the undoubtful role of ROS in the pathology of muscular dystrophies, mdx mice have been used as proof of concept to test possible therapeutic strategies aimed at directly activating NRF2 to ameliorate DMD disease pathology. For example, administration of SFN has been shown to improve the pathology of dystrophic muscles, leading to an increase in muscle strength and mass and reduced inflammation and fibrosis [283,296,297]. (\u2212)-Epicatechin, a flavonoid that activates NRF2 pathway, improved dystrophin-associated protein complex expression and localization in the frontal cortex of mdx mice [298]. The use of this same compound has been also evaluated in other models of muscle dystrophies, including \u03B4-KO [299], a model for limb girdle muscular dystrophies (LGMD), a group of disorders characterized by weakness and atrophy of the limb and shoulder girdle muscles and that is linked to mutations in different genes, such as LMNA (encoding LAMIN A), CAPN3 (encoding calpain 3), DYSF (encoding dysferlin) and SGCA-D (encoding sarcoglycan complex components A-D) [300]. (\u2212)-Epicatechin treatment of \u03B4-KO mice enhanced overall muscle function, possibly by contributing to improve antioxidant response, to decrease apoptosis and to reduce fibrosis [299]. The positive effect of (\u2212)-epicatechin was also shown in a model of BaCl2-induced muscle damage, where the improvement on muscle repair was also evident [301]. Another NRF2 activator, resveratrol, has been shown to improve muscle mass gain, counter oxidative damage, reduce cardiomyopathy and restore mitophagy in mdx mice [302\u2013305]. The mTOR inhibitor and activator of the NRF2 pathway, rapamycin, has also been used to ameliorate the pathophysiology in different models of muscular dystrophy [306,307]. For example, for DMD the treatment of mdx mice with rapamycin led to a reduction in muscle fiber necrosis, increased muscle regeneration, increase in skeletal muscle strength and cardiac contractility [306,308]. Myf5Cre/+, FktnL/L is a fukutin-deficient mouse model of dystroglycanopathy, also known as Fukuyama muscular dystrophy. This model allows the conditional deletion of the Fktn gene, encoding the transmembrane protein fukutin, which locates to the Golgi and is involved in the glycosylation of different proteins, possibly including \u03B1-dystroglycan. Deletion of Fktn only occurs in cells that express Myf5, an important marker for muscle development, where Cre recombinase is conditionally expressed. Rapamycin treatment of Myf5Cre/+, FktnL/L mice allowed to reduce the levels of fibrosis and inflammation, decreased activity-induced damage, and led to a reduction in the central nucleation and increased size of muscle fibers [307]. In Lmna\u2212/\u2212 mice, which lack LAMIN A/C, an important protein to maintain nuclear structure, rapamycin treatment improved cardiac and skeletal muscle function and increased survival [309]. The specific contribution of NRF2 to rapamycin beneficial outcomes should be addressed in future studies.While there is some data supporting a beneficial effect on NRF2 against AMD, a translational approach using preclinical models is lacking. Evidence suggests that protecting the retina from oxidative stress-induced injury is crucial for managing dry AMD. A recent study showed that overexpression of NRF2 in the RPE with an AAV construct produces a robust rescue effect in a mouse model of retinitis pigmentosa. NRF2 overexpression preserved RPE morphology and upregulated multiple oxidative defense pathways. These are the same pathways that are implicated in the pathogenesis of AMD, suggesting that NRF2 overexpression may be a potential therapeutic strategy to slow the pathogenesis of this disease [408].In summary, there is mounting clinical and experimental evidence supporting chronic oxidative stress as a driving force in AMD pathology (Table 11). Therefore, understanding the pathways counteracting oxidative stress in the RPE, especially the NRF2 pathway, in the context of aging, will provide new therapeutic strategies for AMD.Research in the authors' laboratories is funded as follows: AIR and AC by the Spanish Ministry of Science, Innovation and Universities (PID2019-110061RB-I00, PID-2021-122766OB-100, PDC2021-121421-I00, PDC2022-133765-I00), CIBERNED/ISCIII (CB06/05/0010), and The Autonomous Community of Madrid (P2022/BMD-7230). MGL is funded by Spanish Ministry of Science, Innovation and Universities (PID2021-125986OB-I00, PDC2022-133809-I00) and Community of Madrid Ref. P2022/BMD-7230-CAM-22. PR is funded by Spanish Ministry of Science, Innovation and Universities (PID2023-150994OB-I00), The Autonomous Community of Madrid (P2022/BMD-7227) and CIBERDEM/ISCIII (CB07/08/0033). JJV is holder of a FPU contract of Spanish Ministry of Science, Innovation and Universities (FPU20/03326). ILB is funded by the Spanish Ministry of Science, Innovation and Universities (PID2022-137065OB-100, PCD2022-133774-100) and CIBERNED/ISCIII (CB06/05/0089). MCS, ST and ASF are funded by Funda\u00E7\u00E3o para a Ci\u00EAncia e a Tecnologia through R&D unit iNOVA4Health (UIDB/04462/2020 and UIDP/04462/2020) and LS4FUTURE Associated Laboratory (LA/P/0087/2020). ASF is holder of a post-doctoral contract from \u201CLa Caixa Foundation\u201D (NASCENT HR22-00569). IM received research core funding by Slovenian Research Agency (P3-0019). AG received research funding from the National Science Centre grant OPUS (2021/43/B/NZ4/02130). ARC is supported by the donor Henrique Meirelles who chose to support the MATRIHEALTH Project (CC1036), Funda\u00E7\u00E3o para a Ci\u00EAncia e a Tecnologia Project (https://doi.org/10.54499/PTDC/BTM-ORG/1383/2020) and Unit Funding (https://doi.org/10.54499/UIDB/00329/2020). IPT acknowledges funding from NKUA SARG (C.S. 19067). SC is funded by the ISCIII (PI23/01846). LVM is a grant holder of a contract \u041A\u041F-06-\u041A\u041E\u0421\u0422/4 of the Bulgarian National Science Fund under BG-175467353-2023-03 programme. LVM and MIG have received funding from the European Union's Horizon 2020 research and innovation programme, project PlantaSYST (SGA No 739582 under FPA No. 664620) and by the European Regional Development Fund through the Bulgarian \u201CScience and Education for Smart Growth\u201D Operational Programme (BG05M2OP001-1.003-001-C01) and Programme Research Innovation and Digitalisation for Smart Transformation. OK is funded by the European Union Horizon's research and innovation program HORIZON-HLTH-2022-STAYHLTH-02 under agreement No 101095679. ADK is funded by the Medical Research Council UK (MR/W023806/1), the Biotechnology and Biological Sciences Research Council UK (BB/T508111/1 and BB/X00029X/1), Tenovus Scotland (T22-08), and the Cunnigham Trust. This article is based upon work from COST Action CA20121, supported by COST (European Cooperation in Science and Technology) (www.cost.eu) (https://benbedphar.org/about-benbedphar/). Publisher Copyright: © 2024 The Authors
Non-communicable chronic diseases (NCDs) are most commonly characterized by age-related loss of homeostasis and/or by cumulative exposures to environmental factors, which lead to low-grade sustained generation of reactive oxygen species (ROS), chronic inflammation and metabolic imbalance. Nuclear factor erythroid 2-like 2 (NRF2) is a basic leucine-zipper transcription factor that regulates the cellular redox homeostasis. NRF2 controls the expression of more than 250 human genes that share in their regulatory regions a cis-acting enhancer termed the antioxidant response element (ARE). The products of these genes participate in numerous functions including biotransformation and redox homeostasis, lipid and iron metabolism, inflammation, proteostasis, as well as mitochondrial dynamics and energetics. Thus, it is possible that a single pharmacological NRF2 modulator might mitigate the effect of the main hallmarks of NCDs, including oxidative, proteostatic, inflammatory and/or metabolic stress. Research on model organisms has provided tremendous knowledge of the molecular mechanisms by which NRF2 affects NCDs pathogenesis. This review is a comprehensive summary of the most commonly used model organisms of NCDs in which NRF2 has been genetically or pharmacologically modulated, paving the way for drug development to combat NCDs. We discuss the validity and use of these models and identify future challenges.
