Dietary GABA induces endogenous synthesis of a novel imidazole peptide homocarnosine in mouse skeletal muscles
Dietary GABA induces endogenous synthesis of a novel imidazole peptide homocarnosine in mouse skeletal muscles
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DOI：
10.1007/s00726-020-02848-x
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发表时间：
2020-05-02
期刊：
影响因子：
3.5
通讯作者：
Yanaka, Noriyuki
中科院分区：
文献类型：
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作者：
Kumrungsee, Thanutchaporn;Arima, Takeshi;Yanaka, Noriyuki
肌肽(β-丙氨酰-L-组氨酸)是一种存在于骨骼肌中的高浓度咪唑二肽，在骨骼肌中起着有益的作用。然而，口服肌肽或β-丙氨酸来提高骨骼肌肌肽水平存在效率低、副作用大等缺点。因此，基于高肌肽与肌肽结构的相似性，我们建议将高肌肽(γ-氨基丁酰-L-组氨酸)作为一种新的骨骼肌咪唑肽的替代物。为诱导小鼠骨骼肌内源性高肌氨酸合成，小鼠在基础饲料中分别添加0、0.5、2或5%的γ-氨基丁酸(GABA)6周。正如预期的那样，在对照组(0%GABA)中，存在微量浓度的GABA和同型肌肽。与对照组相比，2%和5%GABA摄入量组的骨骼肌同型肌氨酸水平显著升高(分别是对照组的10倍，P<；0.01和53倍，P<；0.01)，而0.5%的GABA摄入量组则没有这种影响。GABA摄入量对肌肽、安丝氨酸和β-丙氨酸水平没有影响。给摄入2%GABA的小鼠注射Vigabatrin(GABA转氨酶抑制剂，GABA-T)2周后，肝脏中GABA-T受到抑制。随后，观察到循环中的GABA水平增加了43倍，骨骼肌的同型肌氨酸水平有增加的趋势。因此，可以通过在组织中供应其底物GABA来诱导骨骼肌高肌肽的合成。由于GABA的有效性受GABA-T通过GABA降解来严格调控，因此GABA或β-丙氨酸降解的抑制剂可能成为增加骨骼肌咪唑二肽的新的潜在干预措施。
Carnosine (beta-alanyl-l-histidine) is an imidazole dipeptide present at high concentrations in skeletal muscles, where it plays a beneficial role. However, oral intake of carnosine or beta-alanine to increase skeletal muscle carnosine levels has disadvantages such as low efficiency and side effects. Therefore, we proposed homocarnosine (gamma-aminobutyryl-l-histidine) as a novel alternative imidazole peptide for skeletal muscle based on its structural similarity to carnosine. To induce endogenous homocarnosine synthesis in skeletal muscles, mice were fed a basal diet mixed with 0, 0.5, 2, or 5% gamma-aminobutyric acid (GABA) for 6 weeks. As expected, in the control group (0% GABA), GABA and homocarnosine were present in trace concentrations. Skeletal muscle homocarnosine levels were significantly increased in the 2% and 5% GABA intake groups (tenfold, P < 0.01 and 53-fold, P < 0.01; respectively) relative to those of the control group, whereas 0.5% GABA intake induced no such effect. GABA intake had no effect on the levels of carnosine, anserine, and beta-alanine. Vigabatrin (inhibitor of GABA transaminase (GABA-T)) administration to mice receiving 2% GABA intake for 2 weeks led to GABA-T inhibition in the liver. Subsequently, a 43-fold increase in circulating GABA levels and a tendency increase in skeletal muscle homocarnosine levels were observed. Therefore, skeletal muscle homocarnosine synthesis can be induced by supplying its substrate GABA in tissues. As GABA availability is tightly regulated by GABA-T via GABA degradation, inhibitors of GABA or beta-alanine degradation could be novel potential interventions for increasing skeletal muscle imidazole dipeptides.