文章基本信息

标题：Skeletal-Muscle Metabolic Reprogramming in ALS-SOD1 G93A Mice Predates Disease Onset and Is A Promising Therapeutic Target
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作者：Silvia Scaricamazza ; Illari Salvatori ; Giacomo Giacovazzo 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2020
卷号：23
期号：5
页码：1-37
DOI：10.1016/j.isci.2020.101087
语种：English
出版社：Elsevier
摘要：SummaryPatients with ALS show, in addition to the loss of motor neurons in the spinal cord, brainstem, and cerebral cortex, an abnormal depletion of energy stores alongside hypermetabolism. In this study, we show that bioenergetic defects and muscle remodeling occur in skeletal muscle of the SOD1G93Amouse model of ALS mice prior to disease onset and before the activation of muscle denervation markers, respectively. These changes in muscle physiology were followed by an increase in energy expenditure unrelated to physical activity. Finally, chronic treatment of SOD1G93Amice with Ranolazine, an FDA-approved inhibitor of fatty acid β-oxidation, led to a decrease in energy expenditure in symptomatic SOD1G93Amice, and this occurred in parallel with a robust, albeit temporary, recovery of the pathological phenotype.Graphical AbstractDisplay OmittedHighlights•Metabolic switch use occurs early in the skeletal muscle of SOD1G93Amice•Mitochondrial impairment precedes locomotor deficits and evokes catabolic pathways•Sarcolipin upregulation in presymptomatic SOD1G93Amice precedes hypermetabolism•Pharmacological modulation of hypermetabolism improves locomotor performanceDrugs; Molecular Neuroscience; Cellular Neuroscience