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Atrogin-1, MuRF1, and FoXO, as well as phosphorylated GSK-3β and 4E-BP1 are reduced in skeletal muscle of chronic spinal cord–injured patients

Authors

  • Bertrand Léger PhD,

    1. Institut de Recherche en Réadaptation–Réinsertion, Sion, Switzerland
    2. Clinique Romande de Réadaptation SuvaCare, Sion, Switzerland
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  • Rosalba Senese PhD,

    1. Seconda Universit` degli Studi di Napoli, Dipartimento di Scienze della Vita, Caserta, Italy
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  • Abdul W. Al-Khodairy MD,

    1. Clinique Romande de Réadaptation SuvaCare, Sion, Switzerland
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  • Olivier Dériaz PhD, MD,

    1. Institut de Recherche en Réadaptation–Réinsertion, Sion, Switzerland
    2. Clinique Romande de Réadaptation SuvaCare, Sion, Switzerland
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  • Charles Gobelet MD,

    1. Institut de Recherche en Réadaptation–Réinsertion, Sion, Switzerland
    2. Clinique Romande de Réadaptation SuvaCare, Sion, Switzerland
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  • Jean-Paul Giacobino PhD, MD,

    1. Institut de Recherche en Réadaptation–Réinsertion, Sion, Switzerland
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  • Aaron P. Russell PhD

    Corresponding author
    1. Clinique Romande de Réadaptation SuvaCare, Sion, Switzerland
    2. Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, 221 Burwood Highway, Burwood 3125, Australia
    • Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, 221 Burwood Highway, Burwood 3125, Australia
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Abstract

Chronic complete spinal cord injury (SCI) is associated with severe skeletal muscle atrophy as well several atrophy and physical-inactivity–related comorbidity factors such as diabetes, obesity, lipid disorders, and cardiovascular diseases. Intracellular mechanisms associated with chronic complete SCI-related muscle atrophy are not well understood, and thus their characterization may assist with developing strategies to reduce the risk of comorbidity factors. Therefore, the aim of this study was to determine whether there was an increase in catabolic signaling targets, such as atrogin-1, muscle ring finger-1 (MuRF1), forkhead transcription factor (FoXO), and myostatin, and decreases in anabolic signaling targets, such as insulin-like growth factor (IGF), v-akt murine thymoma viral oncogene (Akt), glycogen synthase kinase-β (GSK-3β), mammalian target of rapamycin (mTOR), eukaryotic initiation factor 4E binding protein 1 (4E-BP1), and p70s6kinase in chronic complete SCI patients. In SCI patients, when compared with controls, there was a significant reduction in mRNA levels of atrogin-1 (59%; P < 0.05), MuRF1 (55%; P < 0.05), and myostatin (46%; P < 0.01), and in protein levels of FoXO1 (72%; P < 0.05), FoXO3a (60%; P < 0.05), and atrogin-1 (36%; P < 0.05). Decreases in the protein levels of IGF-1 (48%; P < 0.001) and phosphorylated GSK-3β (54%; P < 0.05), 4E-BP1 (48%; P < 0.05), and p70s6kinase (60%; P = 0.1) were also observed, the latter three in an Akt- and mTOR-independent manner. Reductions in atrogin-1, MuRF1, FoXO, and myostatin suggest the existence of an internal mechanism aimed at reducing further loss of muscle proteins during chronic SCI. The downregulation of signaling proteins that regulate anabolism, such as IGF, GSK-3β, and 4E-BP1, would reduce the ability to increase protein synthesis rates. Muscle Nerve 40: 69–78, 2009

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