Sarcopenia phenotype and impaired muscle function in male mice with fast-twitch muscle-specific knockout of the androgen receptor.
Sarcopenia phenotype and impaired muscle function in male mice with fast-twitch muscle-specific knockout of the androgen receptor.
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DOI：
10.1073/pnas.2218032120
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发表时间：
2023-01-24
影响因子：
11.1
通讯作者：
Ogawa, Sumito
中科院分区：
文献类型：
--
作者：
Hosoi, Tatsuya;Yakabe, Mitsutaka;Sasakawa, Hiroko;Sasako, Takayoshi;Ueki, Kohjiro;Kato, Shigeaki;Tokuoka, Suzumi M.;Oda, Yoshiya;Abe, Masahiro;Matsumoto, Toshio;Akishita, Masahiro;Ogawa, Sumito
雄激素-AR信号通路对肌肉减少症的有益作用已被指出，但其病因机制仍未解决。少肌症与通常的肌肉萎缩不同，它与纤维类型的转变密切相关。这是我们生成快肌特异性 AR 敲除的新原始小鼠模型的强烈动机之一，以便更好地了解骨骼肌中的 AR 功能。该模型代表了随年龄增长而出现的肌肉减少症的表型，并表明快肌中的 AR 是肌纤维类型组成和功能的主要调节因子。我们还报道了 AR 调节的多胺生物合成对肌肉代谢的重要性。这些见解可能为未来肌肉减少症药物的开发铺平道路。肌少症与正常肌肉萎缩不同，它与肌纤维类型的变化密切相关。雄激素对骨骼肌合成代谢作用的缺乏与肌肉减少症有关。然而，雄激素受体（AR）通路在肌肉减少症中的功能仍然知之甚少。我们生成了一个小鼠模型（快肌特异性 AR 敲除 [fmARKO] 小鼠），其中快肌纤维中的 AR 被选择性删除。在年轻雄性小鼠中，缺失不会导致肌肉质量发生变化，但会降低肌肉力量和抗疲劳能力，并导致比目鱼肌从快肌纤维转变为慢肌纤维（增加 14%，P = 0.02）。中年之后，与对照小鼠相比，雄性fmARKO小鼠的肌肉功能明显减弱，并伴有后肢肌肉质量降低；这种表型与肌肉减少症的进展相似。 fmARKO 小鼠股骨的骨密度显着降低，表明可能存在骨肌减少症。微阵列和基因本体分析显示，在雄性fmARKO小鼠中，多胺生物合成相关基因下调，液相色谱-串联质谱分析和原代培养的肌纤维证实了这一点。在雌性 fmARKO 小鼠中没有观察到与 AR 缺失相关的表型。我们的研究结果表明，AR 通路在向快肌纤维分化以及维持肌肉组成和功能方面具有重要的肌肉类型和性别特异性作用。快肌中的 AR 是肌纤维类型组成和肌肉功能（包括肌肉与骨骼关系）的主要调节者。
The beneficial effects of the androgen–AR signaling pathway on sarcopenia have been pointed out, but the etiologic mechanism remains unsolved. Sarcopenia differs from usual muscle atrophy in that it is closely related to fiber-type shifts. This was one of our strong motivations to generate a new original mouse model of fast-twitch muscle-specific AR knockout in order to better understand the AR function in skeletal muscles. The model represented phenotypes of sarcopenia with aging and showed that the AR in fast-twitch muscles was the dominant regulator of muscle fiber-type composition and function. We also reported the importance of polyamine biosynthesis, which was regulated by AR, on muscle metabolism. These insights may pave the way for future drug development for sarcopenia. Sarcopenia is distinct from normal muscle atrophy in that it is closely related to a shift in the muscle fiber type. Deficiency of the anabolic action of androgen on skeletal muscles is associated with sarcopenia; however, the function of the androgen receptor (AR) pathway in sarcopenia remains poorly understood. We generated a mouse model (fast-twitch muscle-specific AR knockout [fmARKO] mice) in which the AR was selectively deleted in the fast-twitch muscle fibers. In young male mice, the deletion caused no change in muscle mass, but it reduced muscle strength and fatigue resistance and induced a shift in the soleus muscles from fast-twitch fibers to slow-twitch fibers (14% increase, P = 0.02). After middle age, with the control mice, the male fmARKO mice showed much less muscle function, accompanied by lower hindlimb muscle mass; this phenotype was similar to the progression of sarcopenia. The bone mineral density of the femur was significantly reduced in the fmARKO mice, indicating possible osteosarcopenia. Microarray and gene ontology analyses revealed that in male fmARKO mice, there was downregulation of polyamine biosynthesis-related geneswhich was confirmed by liquid chromatography–tandem mass spectrometry assay and the primary cultured myofibers. None of the AR deletion-related phenotypes were observed in female fmARKO mice. Our findings showed that the AR pathway had essential muscle type- and sex-specific roles in the differentiation toward fast-twitch fibers and in the maintenance of muscle composition and function. The AR in fast-twitch muscles was the dominant regulator of muscle fiber-type composition and muscle function, including the muscle–bone relationship.
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影响因子：
4
作者：
Juo LY;Liao WC;Shih YL;Yang BY;Liu AB;Yan YT
通讯作者：
Yan YT
DOI：
10.3390/medsci6010014
发表时间：
2018-02-14
期刊：
Medical sciences (Basel, Switzerland)
影响因子：
--
作者：
Cervelli M;Leonetti A;Duranti G;Sabatini S;Ceci R;Mariottini P
通讯作者：
Mariottini P
DOI：
10.1621/nrs.06008
发表时间：
2008-06-27
期刊：
Nuclear receptor signaling
影响因子：
--
作者：
Claessens F;Denayer S;Van Tilborgh N;Kerkhofs S;Helsen C;Haelens A
通讯作者：
Haelens A
影响因子：
4.8
作者：
Jell, Jason;Merali, Salim;Porter, Carl W.
通讯作者：
Porter, Carl W.
影响因子：
64.8
作者：
Garcia-Prat, Laura;Martinez-Vicente, Marta;Munoz-Canoves, Pura
通讯作者：
Munoz-Canoves, Pura