Singh Abhishek Kumar, Shree Sonal, Chattopadhyay Sourav, Kumar Sudhir, Gurjar Anagha, Kushwaha Sapana, Kumar Harish, Trivedi Arun Kumar, Chattopadhyay Naibedya, Maurya Rakesh, Ramachandran Ravishankar, Sanyal Sabyasachi
Division of Biochemistry, CSIR-Central Drug Research Institute, 10, Janakipuram Extn, Sitapur Road, Lucknow 226031, India.
Division of Molecular and Structural Biology, CSIR-Central Drug Research Institute, 10, Janakipuram Extn, Sitapur Road, Lucknow 226031, India.
Mol Cell Endocrinol. 2017 Jan 5;439:273-285. doi: 10.1016/j.mce.2016.09.013. Epub 2016 Sep 16.
Skeletal muscle atrophy is a debilitating response to several major diseases, muscle disuse and chronic steroid treatment for which currently no therapy is available. Since adiponectin signaling plays key roles in muscle energetics, we assessed if globular adiponectin (gAd) or the small molecule adiponectin mimetic 6-C-β-D-glucopyranosyl-(2S,3S)-(+)-5,7,3',4'-tetrahydroxydihydroflavonol (GTDF) could ameliorate muscle atrophy. Both GTDF and gAd induced C2C12 myoblast differentiation. GTDF and gAd effectively prevented reduction in myotube area and suppressed the expressions of atrophy markers; atrogin-1 and muscle ring finger protein-1 (MuRF1) in models of steroid, cytokine and starvation -induced muscle atrophy. The protective effects of GTDF and gAd were routed through AMPK and AKT activation and thereby stimulation of PPAR gamma coactivator 1α and inhibition of forkhead box O transcription factors. Finally, GTDF and gAd mitigated dexamethasone-induced muscle atrophy in vivo. Together, our results demonstrate that activating adiponectin signaling may be an effective therapeutic strategy against skeletal muscle atrophy.
骨骼肌萎缩是对几种主要疾病、肌肉废用和长期使用类固醇治疗的一种衰弱性反应，目前尚无针对这些情况的治疗方法。由于脂联素信号在肌肉能量代谢中起关键作用，我们评估了球状脂联素（gAd）或小分子脂联素模拟物6-C-β-D-吡喃葡萄糖基-(2S,3S)-(+)-5,7,3',4'-四羟基二氢黄酮醇（GTDF）是否可以改善肌肉萎缩。GTDF和gAd均可诱导C2C12成肌细胞分化。在类固醇、细胞因子和饥饿诱导的肌肉萎缩模型中，GTDF和gAd有效地防止了肌管面积的减小，并抑制了萎缩标志物atrogin-1和肌肉环指蛋白1（MuRF1）的表达。GTDF和gAd的保护作用是通过激活AMPK和AKT，从而刺激PPARγ共激活因子1α并抑制叉头框O转录因子来实现的。最后，GTDF和gAd减轻了地塞米松诱导的体内肌肉萎缩。总之，我们的结果表明，激活脂联素信号可能是对抗骨骼肌萎缩的一种有效治疗策略。
