Files D Clark, Ilaiwy Amro, Parry Traci L, Gibbs Kevin W, Liu Chun, Bain James R, Delbono Osvaldo, Muehlbauer Michael J, Willis Monte S
Internal Medicine-Sections in Pulmonary and Critical Care Medicine and Geriatrics and the Critical Illness Injury and Recovery Research Center, Wake Forest School of Medicine, Winston-Salem, NC USA.
Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA; Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
Metabolomics. 2016 Aug;12(8). doi: 10.1007/s11306-016-1079-5. Epub 2016 Jul 26.
Older patients are more likely to acquire and die from acute respiratory distress syndrome (ARDS) and muscle weakness may be more clinically significant in older persons. Recent data implicate muscle ring finger protein 1 (MuRF1) in lung injury-induced skeletal muscle atrophy in young mice and identify an alternative role for MuRF1 in cardiac metabolism regulation through inhibition of fatty acid oxidation.
To develop a model of lung injury-induced muscle wasting in old mice and to evaluate the skeletal muscle metabolomic profile of adult and old acute lung injury (ALI) mice.
Young (2 month), adult (6 month) and old (20 month) male C57Bl6J mice underwent Sham (intratracheal HO) or ALI [intratracheal lipopolysaccharide (i.t. LPS)] conditions and muscle functional testing. Metabolomic analysis on gastrocnemius muscle was performed using gas chromatography-mass spectrometry (GC-MS).
Old ALI mice had increased mortality and failed to recover skeletal muscle function compared to adult ALI mice. Muscle MuRF1 expression was increased in old ALI mice at day 3. Non-targeted muscle metabolomics revealed alterations in amino acid biosynthesis and fatty acid metabolism in old ALI mice. Targeted metabolomics of fatty acid intermediates (acyl-carnitines) and amino acids revealed a reduction in long chain acyl-carnitines in old ALI mice.
This study demonstrates age-associated susceptibility to ALI-induced muscle wasting which parallels a metabolomic profile suggestive of altered muscle fatty acid metabolism. MuRF1 activation may contribute to both atrophy and impaired fatty acid oxidation, which may synergistically impair muscle function in old ALI mice.
老年患者更易患急性呼吸窘迫综合征（ARDS）并死于该病，且肌肉无力在老年人中可能具有更显著的临床意义。最近的数据表明，肌肉无名指蛋白1（MuRF1）在幼鼠肺损伤诱导的骨骼肌萎缩中起作用，并通过抑制脂肪酸氧化确定了MuRF1在心脏代谢调节中的另一个作用。
建立老年小鼠肺损伤诱导的肌肉萎缩模型，并评估成年和老年急性肺损伤（ALI）小鼠的骨骼肌代谢组学特征。
将年轻（2个月）、成年（6个月）和老年（20个月）雄性C57Bl6J小鼠置于假手术（气管内注入生理盐水）或ALI [气管内注射脂多糖（i.t. LPS）]条件下，并进行肌肉功能测试。使用气相色谱-质谱联用（GC-MS）对腓肠肌进行代谢组学分析。
与成年ALI小鼠相比，老年ALI小鼠死亡率增加，骨骼肌功能未能恢复。在第3天，老年ALI小鼠的肌肉MuRF1表达增加。非靶向肌肉代谢组学显示老年ALI小鼠的氨基酸生物合成和脂肪酸代谢发生改变。脂肪酸中间体（酰基肉碱）和氨基酸的靶向代谢组学显示老年ALI小鼠的长链酰基肉碱减少。
本研究表明，老年小鼠对ALI诱导的肌肉萎缩具有年龄相关性易感性，这与提示肌肉脂肪酸代谢改变的代谢组学特征相似。MuRF1激活可能导致萎缩和脂肪酸氧化受损，这可能协同损害老年ALI小鼠的肌肉功能。
