دورية أكاديمية
Transcriptomics reveals transient and dynamic muscle fibrosis and atrophy differences following spinal cord injury in rats.
| العنوان: | Transcriptomics reveals transient and dynamic muscle fibrosis and atrophy differences following spinal cord injury in rats. |
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| المؤلفون: | Kok HJ; Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, FL, USA.; Research Service, Malcolm Randall Department of Veterans Affairs Medical Center, North Florida/South Georgia Veterans Health System, Gainesville, FL, USA., Fletcher DB; Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, FL, USA., Oster JC; Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, FL, USA., Conover CF; Research Service, Malcolm Randall Department of Veterans Affairs Medical Center, North Florida/South Georgia Veterans Health System, Gainesville, FL, USA., Barton ER; Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, FL, USA., Yarrow JF; Research Service, Malcolm Randall Department of Veterans Affairs Medical Center, North Florida/South Georgia Veterans Health System, Gainesville, FL, USA.; Division of Endocrinology, Diabetes and Metabolism, College of Medicine, University of Florida, Gainesville, FL, USA.; Brain Rehabilitation Research Center, Malcolm Randall Department of Veterans Affairs Medical Center, North Florida/South Georgia Veterans Health System, Gainesville, FL, USA.; Eastern Colorado Geriatrics Research, Education, and Clinical Center, Rocky Mountain Regional Veterans Affairs Medical Center, VA Eastern Colorado Health Care System, Aurora, CO, USA. |
| المصدر: | Journal of cachexia, sarcopenia and muscle [J Cachexia Sarcopenia Muscle] 2024 Aug; Vol. 15 (4), pp. 1309-1323. Date of Electronic Publication: 2024 May 19. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders Country of Publication: Germany NLM ID: 101552883 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2190-6009 (Electronic) Linking ISSN: 21905991 NLM ISO Abbreviation: J Cachexia Sarcopenia Muscle Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2015- : Berlin : John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders Original Publication: Heidelburg : Springer-Verlag |
| مواضيع طبية MeSH: | Spinal Cord Injuries*/complications , Spinal Cord Injuries*/metabolism , Spinal Cord Injuries*/pathology , Spinal Cord Injuries*/genetics , Fibrosis* , Muscular Atrophy*/metabolism , Muscular Atrophy*/etiology , Muscular Atrophy*/pathology , Muscular Atrophy*/genetics, Animals ; Rats ; Male ; Transcriptome ; Rats, Sprague-Dawley ; Disease Models, Animal ; Muscle, Skeletal/pathology ; Muscle, Skeletal/metabolism ; Gene Expression Profiling |
| مستخلص: | Background: The rate and magnitude of skeletal muscle wasting after severe spinal cord injury (SCI) exceeds most other disuse conditions. Assessing the time course of molecular changes can provide insight into the progression of muscle wasting post-SCI. The goals of this study were (1) to identify potential targets that may prevent the pathologic features of SCI in soleus muscles and (2) to establish therapeutic windows for treating these pathologic changes. Methods: Four-month-old Sprague-Dawley male rats received T9 laminectomy (SHAM surgery) or severe contusion SCI. Hindlimb locomotor function was assessed weekly, with soleus muscles obtained 1 week, 2 weeks, 1 month and 3 months post-surgery (n = 6-7 per group per timepoint). RNA was extracted from muscles for bulk RNA-sequencing analysis (n = 3-5 per group per timepoint). Differentially expressed genes (DEGs) were evaluated between age-matched SHAM and SCI animals. Myofiber size, muscle fibre type and fibrosis were assessed on contralateral muscles. Results: SCI produced immediate and persistent hindlimb paralysis, with Basso-Beattie-Bresnahan locomotor scores remaining below 7 throughout the study, contributing to a progressive 25-50% lower soleus mass and myofiber atrophy versus SHAM (P < 0.05 at all timepoints). Transcriptional comparisons of SCI versus SHAM resulted in 184 DEGs (1 week), 436 DEGs (2 weeks), 133 DEGs (1 month) and 1200 DEGs (3 months). Upregulated atrophy-related genes included those associated with cell senescence, nuclear factor kappa B, ubiquitin proteasome and unfolded protein response pathways, along with upregulated genes that negatively influence muscle growth through the transforming growth factor beta pathway and inhibition of insulin-like growth factor-I/Akt/mechanistic target of rapamycin and p38/mitogen-activated protein kinase signalling. Genes associated with extracellular matrix (ECM), including collagens, collagen crosslinkers, proteoglycans and those regulating ECM integrity, were enriched within upregulated DEGs at 1 week but subsequently downregulated at 2 weeks and 3 months and were accompanied by >50% higher ECM areas and hydroxyproline levels in SCI muscles (P < 0.05). Myofiber remodelling genes were enriched in upregulated DEGs at 2 weeks and 1 month and were downregulated at 3 months. Genes that regulate neuromuscular junction remodelling were evident in muscles post-SCI, along with slow-to-fast fibre-type shifts: 1 week and 2 weeks SCI muscles were composed of 90% myosin heavy chain (MHC) type I fibres, which decreased to only 16% at 3 months and were accompanied by 50% fibres containing MHC IIX (P < 0.05). Metabolism genes were enriched in upregulated DEGs at 1 month and were further enriched at 3 months. Conclusions: Our results substantiate many known pathologic features of SCI-induced wasting in rat skeletal muscle and identify a progressive and dynamic transcriptional landscape within the post-SCI soleus. Future studies are warranted to consider these therapeutic treatment windows when countering SCI muscle pathology. (© 2024 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.) |
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| معلومات مُعتمدة: | K00 AG068438 United States AG NIA NIH HHS; Undergraduate Scholars Program, University of Florida; I01 RX002447 United States RX RRD VA; F99 AG068438 United States AG NIA NIH HHS; P50 AR052646 United States AR NIAMS NIH HHS; F99AG068438 US National Institutes of Health (NIH); 1I21RX001373-01 Department of Veterans Affairs Office of Research and Development, Rehabilitation Research and Development Service; North Florida/South Georgia Veterans Health System; I21 RX001373 United States RX RRD VA; PECASE B9280-O Department of Veterans Affairs Office of Research and Development, Rehabilitation Research and Development Service |
| فهرسة مساهمة: | Keywords: RNA‐sequencing; disuse atrophy; extracellular matrix remodelling; muscle fibre‐type shift; soleus muscle wasting; spinal cord injury |
| تواريخ الأحداث: | Date Created: 20240520 Date Completed: 20240801 Latest Revision: 20240804 |
| رمز التحديث: | 20240804 |
| مُعرف محوري في PubMed: | PMC11294049 |
| DOI: | 10.1002/jcsm.13476 |
| PMID: | 38764311 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2190-6009 |
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| DOI: | 10.1002/jcsm.13476 |