Disturbed energy metabolism and muscular dystrophy caused by pure creatine deficiency are reversible by creatine intake
Disturbed energy metabolism and muscular dystrophy caused by pure creatine deficiency are reversible by creatine intake
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DOI：
10.1113/jphysiol.2012.241760
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发表时间：
2013-01-01
影响因子：
5.5
通讯作者：
Heerschap, A.
中科院分区：
文献类型：
--
作者：
Nabuurs, C. I.;Choe, C. U.;Heerschap, A.
肌酸 (Cr) 通过参与肌酸激酶介导的 ATP-磷酸肌酸磷酰基交换反应，在肌肉能量稳态中发挥重要作用。鉴于 Cr 消耗的后果尚不完全清楚，我们在缺乏 L-精氨酸：甘氨酸脒基转移酶 (AGAT(-/-)) 的小鼠模型中评估了系统性消耗对骨骼肌的形态、代谢和功能影响，该酶催化 Cr 生物合成的第一步。体内磁共振波谱显示 AGAT(-/-) 小鼠静息后肢肌肉几乎完全不存在 Cr 和磷酸肌酸。与野生型相比，无机磷酸盐/β-ATP比率增加了四倍，而ATP水平降低了近一半。质子泵呼吸链酶的活性降低，而F1F0-ATP酶活性和线粒体总含量增加。缺乏 Cr 的 AGAT(-/-) 小鼠的握力下降，并出现严重的肌肉萎缩。电子显微镜显示 AGAT(-/-) 肌纤维线粒体内的肌细胞内脂滴和晶体形成量增加。缺血导致 pH 值下降加剧和糖酵解 ATP 合成增加。口服Cr导致骨骼肌中的快速积累（比大脑中更快）并逆转所有肌肉异常，表明AGAT（-/-）小鼠的状况可以通过饮食控制在Cr缺乏和正常之间切换。全身肌酸消耗导致线粒体功能障碍和细胞内能量缺乏，以及结构和生理异常。 AGAT 缺乏的后果比肌肉特异性肌酸激酶缺乏的后果更明显，这表明肌酸除了在磷酸肌酸-肌酸激酶系统中发挥作用外，还多方面参与肌肉能量稳态。
Creatine (Cr) plays an important role in muscle energy homeostasis by its participation in the ATP-phosphocreatine phosphoryl exchange reaction mediated by creatine kinase. Given that the consequences of Cr depletion are incompletely understood, we assessed the morphological, metabolic and functional consequences of systemic depletion on skeletal muscle in a mouse model with deficiency of L-arginine: glycine amidinotransferase (AGAT(-/-)), which catalyses the first step of Cr biosynthesis. In vivo magnetic resonance spectroscopy showed a near-complete absence of Cr and phosphocreatine in resting hindlimb muscle of AGAT(-/-) mice. Compared with wild-type, the inorganic phosphate/beta-ATP ratio was increased fourfold, while ATP levels were reduced by nearly half. Activities of proton-pumping respiratory chain enzymes were reduced, whereas F1F0-ATPase activity and overall mitochondrial content were increased. The Cr-deficient AGAT(-/-) mice had a reduced grip strength and suffered from severe muscle atrophy. Electron microscopy revealed increased amounts of intramyocellular lipid droplets and crystal formation within mitochondria of AGAT(-/-) muscle fibres. Ischaemia resulted in exacerbation of the decrease of pH and increased glycolytic ATP synthesis. Oral Cr administration led to rapid accumulation in skeletal muscle (faster than in brain) and reversed all the muscle abnormalities, revealing that the condition of the AGAT(-/-) mice can be switched between Cr deficient and normal simply by dietary manipulation. Systemic creatine depletion results in mitochondrial dysfunction and intracellular energy deficiency, as well as structural and physiological abnormalities. The consequences of AGAT deficiency are more pronounced than those of muscle-specific creatine kinase deficiency, which suggests a multifaceted involvement of creatine in muscle energy homeostasis in addition to its role in the phosphocreatine-creatine kinase system.