Urszula Florczyk-Soluch, Katarzyna Polak, Sarka Jelinkova, Iwona Bronisz-Budzyńska, Reece Sabo, Subhashini Bolisetty, Anupam Agarwal, Ewa Werner, Alicja Józkowicz, Jacek Stępniewski, Krzysztof Szade, Józef Dulak
{"title":"在卫星细胞中靶向表达血红素加氧酶-1可改善营养不良小鼠的骨骼肌病理变化。","authors":"Urszula Florczyk-Soluch, Katarzyna Polak, Sarka Jelinkova, Iwona Bronisz-Budzyńska, Reece Sabo, Subhashini Bolisetty, Anupam Agarwal, Ewa Werner, Alicja Józkowicz, Jacek Stępniewski, Krzysztof Szade, Józef Dulak","doi":"10.1186/s13395-024-00346-2","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Adult muscle-resident myogenic stem cells, satellite cells (SCs), that play non-redundant role in muscle regeneration, are intrinsically impaired in Duchenne muscular dystrophy (DMD). Previously we revealed that dystrophic SCs express low level of anti-inflammatory and anti-oxidative heme oxygenase-1 (HO-1, HMOX1). Here we assess whether targeted induction of HMOX1 affect SC function and alleviates hallmark symptoms of DMD.</p><p><strong>Methods: </strong>We generated double-transgenic mouse model (mdx;HMOX1<sup>Pax7Ind</sup>) that allows tamoxifen (TX)-inducible HMOX1 expression in Pax7 positive cells of dystrophic muscles. Mdx;HMOX1<sup>Pax7Ind</sup> and control mdx mice were subjected to 5-day TX injections (75 mg/kg b.w.) followed by acute exercise protocol with high-speed treadmill (12 m/min, 45 min) and downhill running to worsen skeletal muscle phenotype and reveal immediate effects of HO-1 on muscle pathology and SC function.</p><p><strong>Results: </strong>HMOX1 induction caused a drop in SC pool in mdx;HMOX1<sup>Pax7Ind</sup> mice (vs. mdx counterparts), while not exaggerating the effect of physical exercise. Upon physical exercise, the proliferation of SCs and activated CD34<sup>-</sup> SC subpopulation, was impaired in mdx mice, an effect that was reversed in mdx;HMOX1<sup>Pax7Ind</sup> mice, however, both in vehicle- and TX-treated animals. This corresponded to the pattern of HO-1 expression in skeletal muscles. At the tissue level, necrotic events of selective skeletal muscles of mdx mice and associated increase in circulating levels of muscle damage markers were blunted in HO-1 transgenic animals which showed also anti-inflammatory cytokine profile (vs. mdx).</p><p><strong>Conclusions: </strong>Targeted expression of HMOX1 plays protective role in DMD and alleviates dystrophic muscle pathology.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":5.3000,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11167827/pdf/","citationCount":"0","resultStr":"{\"title\":\"Targeted expression of heme oxygenase-1 in satellite cells improves skeletal muscle pathology in dystrophic mice.\",\"authors\":\"Urszula Florczyk-Soluch, Katarzyna Polak, Sarka Jelinkova, Iwona Bronisz-Budzyńska, Reece Sabo, Subhashini Bolisetty, Anupam Agarwal, Ewa Werner, Alicja Józkowicz, Jacek Stępniewski, Krzysztof Szade, Józef Dulak\",\"doi\":\"10.1186/s13395-024-00346-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Adult muscle-resident myogenic stem cells, satellite cells (SCs), that play non-redundant role in muscle regeneration, are intrinsically impaired in Duchenne muscular dystrophy (DMD). Previously we revealed that dystrophic SCs express low level of anti-inflammatory and anti-oxidative heme oxygenase-1 (HO-1, HMOX1). Here we assess whether targeted induction of HMOX1 affect SC function and alleviates hallmark symptoms of DMD.</p><p><strong>Methods: </strong>We generated double-transgenic mouse model (mdx;HMOX1<sup>Pax7Ind</sup>) that allows tamoxifen (TX)-inducible HMOX1 expression in Pax7 positive cells of dystrophic muscles. Mdx;HMOX1<sup>Pax7Ind</sup> and control mdx mice were subjected to 5-day TX injections (75 mg/kg b.w.) followed by acute exercise protocol with high-speed treadmill (12 m/min, 45 min) and downhill running to worsen skeletal muscle phenotype and reveal immediate effects of HO-1 on muscle pathology and SC function.</p><p><strong>Results: </strong>HMOX1 induction caused a drop in SC pool in mdx;HMOX1<sup>Pax7Ind</sup> mice (vs. mdx counterparts), while not exaggerating the effect of physical exercise. Upon physical exercise, the proliferation of SCs and activated CD34<sup>-</sup> SC subpopulation, was impaired in mdx mice, an effect that was reversed in mdx;HMOX1<sup>Pax7Ind</sup> mice, however, both in vehicle- and TX-treated animals. This corresponded to the pattern of HO-1 expression in skeletal muscles. At the tissue level, necrotic events of selective skeletal muscles of mdx mice and associated increase in circulating levels of muscle damage markers were blunted in HO-1 transgenic animals which showed also anti-inflammatory cytokine profile (vs. mdx).</p><p><strong>Conclusions: </strong>Targeted expression of HMOX1 plays protective role in DMD and alleviates dystrophic muscle pathology.</p>\",\"PeriodicalId\":21747,\"journal\":{\"name\":\"Skeletal Muscle\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.3000,\"publicationDate\":\"2024-06-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11167827/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Skeletal Muscle\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s13395-024-00346-2\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Skeletal Muscle","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13395-024-00346-2","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Targeted expression of heme oxygenase-1 in satellite cells improves skeletal muscle pathology in dystrophic mice.
Background: Adult muscle-resident myogenic stem cells, satellite cells (SCs), that play non-redundant role in muscle regeneration, are intrinsically impaired in Duchenne muscular dystrophy (DMD). Previously we revealed that dystrophic SCs express low level of anti-inflammatory and anti-oxidative heme oxygenase-1 (HO-1, HMOX1). Here we assess whether targeted induction of HMOX1 affect SC function and alleviates hallmark symptoms of DMD.
Methods: We generated double-transgenic mouse model (mdx;HMOX1Pax7Ind) that allows tamoxifen (TX)-inducible HMOX1 expression in Pax7 positive cells of dystrophic muscles. Mdx;HMOX1Pax7Ind and control mdx mice were subjected to 5-day TX injections (75 mg/kg b.w.) followed by acute exercise protocol with high-speed treadmill (12 m/min, 45 min) and downhill running to worsen skeletal muscle phenotype and reveal immediate effects of HO-1 on muscle pathology and SC function.
Results: HMOX1 induction caused a drop in SC pool in mdx;HMOX1Pax7Ind mice (vs. mdx counterparts), while not exaggerating the effect of physical exercise. Upon physical exercise, the proliferation of SCs and activated CD34- SC subpopulation, was impaired in mdx mice, an effect that was reversed in mdx;HMOX1Pax7Ind mice, however, both in vehicle- and TX-treated animals. This corresponded to the pattern of HO-1 expression in skeletal muscles. At the tissue level, necrotic events of selective skeletal muscles of mdx mice and associated increase in circulating levels of muscle damage markers were blunted in HO-1 transgenic animals which showed also anti-inflammatory cytokine profile (vs. mdx).
Conclusions: Targeted expression of HMOX1 plays protective role in DMD and alleviates dystrophic muscle pathology.
期刊介绍:
The only open access journal in its field, Skeletal Muscle publishes novel, cutting-edge research and technological advancements that investigate the molecular mechanisms underlying the biology of skeletal muscle. Reflecting the breadth of research in this area, the journal welcomes manuscripts about the development, metabolism, the regulation of mass and function, aging, degeneration, dystrophy and regeneration of skeletal muscle, with an emphasis on understanding adult skeletal muscle, its maintenance, and its interactions with non-muscle cell types and regulatory modulators.
Main areas of interest include:
-differentiation of skeletal muscle-
atrophy and hypertrophy of skeletal muscle-
aging of skeletal muscle-
regeneration and degeneration of skeletal muscle-
biology of satellite and satellite-like cells-
dystrophic degeneration of skeletal muscle-
energy and glucose homeostasis in skeletal muscle-
non-dystrophic genetic diseases of skeletal muscle, such as Spinal Muscular Atrophy and myopathies-
maintenance of neuromuscular junctions-
roles of ryanodine receptors and calcium signaling in skeletal muscle-
roles of nuclear receptors in skeletal muscle-
roles of GPCRs and GPCR signaling in skeletal muscle-
other relevant aspects of skeletal muscle biology.
In addition, articles on translational clinical studies that address molecular and cellular mechanisms of skeletal muscle will be published. Case reports are also encouraged for submission.
Skeletal Muscle reflects the breadth of research on skeletal muscle and bridges gaps between diverse areas of science for example cardiac cell biology and neurobiology, which share common features with respect to cell differentiation, excitatory membranes, cell-cell communication, and maintenance. Suitable articles are model and mechanism-driven, and apply statistical principles where appropriate; purely descriptive studies are of lesser interest.