Angiotensin-converting enzyme 2 deficiency accelerates and angiotensin 1-7 restores age-related muscle weakness in mice.
Angiotensin-converting enzyme 2 deficiency accelerates and angiotensin 1-7 restores age-related muscle weakness in mice.
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DOI：
10.1002/jcsm.12334
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Rakugi H
中科院分区：
文献类型：
--
作者：
Takeshita H;Yamamoto K;Nozato S;Takeda M;Fukada SI;Inagaki T;Tsuchimochi H;Shirai M;Nozato Y;Fujimoto T;Imaizumi Y;Yokoyama S;Nagasawa M;Hamano G;Hongyo K;Kawai T;Hanasaki-Yamamoto H;Takeda S;Takahashi T;Akasaka H;Itoh N;Takami Y;Takeya Y;Sugimoto K;Nakagami H;Rakugi H
需要针对年龄相关性肌无力的药理学策略来改善老年人的死亡率和残疾。血管紧张素转换酶2（ACE 2）将血管紧张素II裂解为血管紧张素1 - 7，这是一种已知可保护啮齿动物免受急性和慢性骨骼肌损伤的肽。由于生理性衰老通过与其他肌肉疾病不同的机制诱导肌无力，因此ACE 2-血管紧张素1 - 7在年龄相关性肌无力中的作用尚未确定。在这里，我们研究了ACE 2的缺失是否会改变衰老引起的肌无力的发展，以及血管紧张素1 - 7是否会逆转老年小鼠的肌无力。在定期测量雄性ACE 2KO和野生型小鼠的握力和跑步距离直至24月龄后，我们输注血管紧张素1 - 7或溶媒4周，并测量握力和切除组织。还从年轻（3月龄）和中年（15月龄）小鼠中切除组织。使用来自中年小鼠的胫骨前肌（TA）进行RNA的微阵列分析，并使用RT-PCR进一步测试一些基因。ACE 2KO小鼠的握力在6个月时降低，并且持续低于野生型小鼠（在6、12、18和24个月大时p < 0.01）。ACE 2KO小鼠的跑步距离仅在24月龄时比野生型小鼠短[371 ± 26 vs. 479 ± 24（m），p < 0.01]。血管紧张素1 - 7改善了两种类型老年小鼠的握力，在ACE 2KO小鼠中观察到更大的影响（野生型和ACE 2KO小鼠中分别增加3.8 ± 1.5和13.3 ± 3.1%）。通过代谢笼评估，年龄较大但非中年ACE 2KO小鼠的耗氧量高于年龄匹配的野生型小鼠。血管紧张素1 - 7输注适度增加老年小鼠的耗氧量。ACE 2KO和野生型小鼠之间以及接受溶媒和血管紧张素1 - 7输注的小鼠之间的转轮活动或葡萄糖耐量无差异。TA肌肉的分析显示，p16 INK 4a（一种衰老相关基因）和肌纤维的中央核在中年小鼠中增加，但在年轻的ACE 2KO小鼠中没有增加。老年野生型小鼠的TA肌肉中p16 INK 4a和中央核增加，但ACE 2KO和野生型小鼠之间的差异仍然显著（p < 0.01）。血管紧张素1 - 7没有改变两种小鼠TA肌肉中p16 INK 4a或中央核的表达。野生型小鼠的肌肉ACE 2表达在中年时最低（比年轻时低2.6倍，p < 0.05）。ACE 2的缺失诱导了具有肌肉衰老特征的肌无力的早期表现。血管紧张素1 - 7改善了老年小鼠的肌肉功能，支持该肽或其类似物在老年人群中治疗肌无力的未来应用。
A pharmacologic strategy for age‐related muscle weakness is desired to improve mortality and disability in the elderly. Angiotensin‐converting enzyme 2 (ACE2) cleaves angiotensin II into angiotensin 1‐7, a peptide known to protect against acute and chronic skeletal muscle injury in rodents. Since physiological aging induces muscle weakness via mechanisms distinct from other muscle disorders, the role of ACE2‐angiotensin 1‐7 in age‐related muscle weakness remains undetermined. Here, we investigated whether deletion of ACE2 alters the development of muscle weakness by aging and whether angiotensin 1‐7 reverses muscle weakness in older mice. After periodic measurement of grip strength and running distance in male ACE2KO and wild‐type mice until 24 months of age, we infused angiotensin 1‐7 or vehicle for 4 weeks, and measured grip strength, and excised tissues. Tissues were also excised from younger (3‐month‐old) and middle‐aged (15‐month‐old) mice. Microarray analysis of RNA was performed using tibialis anterior (TA) muscles from middle‐aged mice, and some genes were further tested using RT‐PCR. Grip strength of ACE2KO mice was reduced at 6 months and was persistently lower than that of wild‐type mice (p < 0.01 at 6, 12, 18, and 24‐month‐old). Running distance of ACE2KO mice was shorter than that of wild‐type mice only at 24 months of age [371 ± 26 vs. 479 ± 24 (m), p < 0.01]. Angiotensin 1‐7 improved grip strength in both types of older mice, with larger effects observed in ACE2KO mice (% increase, 3.8 ± 1.5 and 13.3 ± 3.1 in wild type and ACE2KO mice, respectively). Older, but not middle‐aged ACE2KO mice had higher oxygen consumption assessed by a metabolic cage than age‐matched wild‐type mice. Angiotensin 1‐7 infusion modestly increased oxygen consumption in older mice. There was no difference in a wheel‐running activity or glucose tolerance between ACE2KO and wild‐type mice and between mice with vehicle and angiotensin 1‐7 infusion. Analysis of TA muscles revealed that p16INK4a, a senescence‐associated gene, and central nuclei of myofibers increased in middle‐aged, but not younger ACE2KO mice. p16INK4a and central nuclei increased in TA muscles of older wild‐type mice, but the differences between ACE2KO and wild‐type mice remained significant (p < 0.01). Angiotensin 1‐7 did not alter the expression of p16INK4a or central nuclei in TA muscles of both types of mice. Muscle ACE2 expression of wild‐type mice was the lowest at middle age (2.6 times lower than younger age, p < 0.05). Deletion of ACE2 induced the early manifestation of muscle weakness with signatures of muscle senescence. Angiotensin 1‐7 improved muscle function in older mice, supporting future application of the peptide or its analogues in the treatment of muscle weakness in the elderly population.
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影响因子：
4.3
作者：
Morales MG;Abrigo J;Acuña MJ;Santos RA;Bader M;Brandan E;Simon F;Olguin H;Cabrera D;Cabello-Verrugio C
通讯作者：
Cabello-Verrugio C
ACE2将氨基酸营养不良与微生物生态学和肠炎联系起来。
影响因子：
64.8
作者：
Hashimoto T;Perlot T;Rehman A;Trichereau J;Ishiguro H;Paolino M;Sigl V;Hanada T;Hanada R;Lipinski S;Wild B;Camargo SM;Singer D;Richter A;Kuba K;Fukamizu A;Schreiber S;Clevers H;Verrey F;Rosenstiel P;Penninger JM
通讯作者：
Penninger JM
影响因子：
29
作者：
Ellacott KL;Morton GJ;Woods SC;Tso P;Schwartz MW
通讯作者：
Schwartz MW
影响因子：
64.5
作者：
Narkar VA;Downes M;Yu RT;Embler E;Wang YX;Banayo E;Mihaylova MM;Nelson MC;Zou Y;Juguilon H;Kang H;Shaw RJ;Evans RM
通讯作者：
Evans RM
DOI：
10.1007/s00198-017-3980-9
发表时间：
2017-06
期刊：
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA
影响因子：
--
作者：
Beaudart C;Dawson A;Shaw SC;Harvey NC;Kanis JA;Binkley N;Reginster JY;Chapurlat R;Chan DC;Bruyère O;Rizzoli R;Cooper C;Dennison EM;IOF-ESCEO Sarcopenia Working Group
通讯作者：
IOF-ESCEO Sarcopenia Working Group