Endocrinology, Diabetes and Nutrition Unit, Institute of Experimental and Clinical Research, Medical Sector, Université Catholique de Louvain, Brussels, Belgium.
J Cachexia Sarcopenia Muscle. 2020 Apr;11(2):518-533. doi: 10.1002/jcsm.12531. Epub 2020 Jan 21.
Adiponectin (ApN) is a hormone known to exhibit insulin-sensitizing, fat-burning, and anti-inflammatory properties in several tissues, including the skeletal muscle. Duchenne muscular dystrophy (DMD) is a devastating disease characterized by dystrophin deficiency with subsequent chronic inflammation, myofiber necrosis, and impaired regeneration. Previously, we showed that transgenic up-regulation of ApN could significantly attenuate the dystrophic phenotype in mdx mice (model of DMD). Recently, an orally active ApN receptor agonist, AdipoRon, has been identified. This synthetic small molecule has the advantage of being more easily produced and administrable than ApN. The aim of this study was to investigate the potential effects of AdipoRon on the dystrophic muscle.
Four-week-old mdx mice (n = 6-9 per group) were orally treated with AdipoRon (mdx-AR) for 8 weeks and compared with untreated (mdx) mice and to control (wild-type) mice. In vivo functional tests were carried out to measure the global force and endurance of mice. Ex vivo biochemical and molecular analyses were performed to evaluate the pathophysiology of the skeletal muscle. Finally, in vitro tests were conducted on primary cultures of healthy and DMD human myotubes.
AdipoRon treatment mitigated oxidative stress (-30% to 45% for 4-hydroxy-2-nonenal and peroxiredoxin 3, P < 0.0001) as well as inflammation in muscles of mdx mice (-35% to 65% for interleukin 1 beta, tumour necrosis factor alpha, and cluster of differentiation 68, a macrophage maker, P < 0.0001) while increasing the anti-inflammatory cytokine, interleukin 10 (~5-fold, P < 0.0001). AdipoRon also improved the myogenic programme as assessed by a ~2-fold rise in markers of muscle proliferation and differentiation (P < 0.01 or less vs. untreated mdx). Plasma lactate dehydrogenase and creatine kinase were reduced by 30-40% in mdx-AR mice, reflecting less sarcolemmal damage (P < 0.0001). When compared with untreated mdx mice, mdx-AR mice exhibited enhanced physical performance with an increase in both muscle force and endurance and a striking restoration of the running capacity during eccentric exercise. AdipoRon mainly acted through ApN receptor 1 by increasing AMP-activated protein kinase signalling, which led to repression of nuclear factor-kappa B, up-regulation of utrophin (a dystrophin analogue), and a switch towards an oxidative and more resistant fibre phenotype. The effects of AdipoRon were then recapitulated in human DMD myotubes.
These results demonstrate that AdipoRon exerts several beneficial effects on the dystrophic muscle. This molecule could offer promising therapeutic prospect for managing DMD or other muscle and inflammatory disorders.
脂联素（ApN）是一种激素，已知在包括骨骼肌在内的几种组织中具有胰岛素增敏、燃脂和抗炎作用。杜氏肌营养不良症（DMD）是一种破坏性疾病，其特征是肌营养不良蛋白缺乏，随后发生慢性炎症、肌纤维坏死和受损再生。此前，我们表明，ApN 的转基因上调可显著减轻 mdx 小鼠（DMD 模型）的营养不良表型。最近，一种口服有效的 ApN 受体激动剂 AdipoRon 已被鉴定出来。这种合成的小分子具有比 ApN 更容易生产和管理的优点。本研究的目的是研究 AdipoRon 对营养不良肌肉的潜在影响。
4 周龄 mdx 小鼠（每组 6-9 只）经口给予 AdipoRon（mdx-AR）治疗 8 周，并与未治疗（mdx）小鼠和对照（野生型）小鼠进行比较。进行体内功能测试以测量小鼠的整体力和耐力。进行离体生化和分子分析以评估骨骼肌的病理生理学。最后，在健康和 DMD 人类肌管的原代培养物上进行体外测试。
AdipoRon 治疗减轻了 mdx 小鼠肌肉中的氧化应激（4- 羟基-2-壬烯醛和过氧化物酶 3 减少 30%至 45%，P < 0.0001）和炎症（白细胞介素 1β、肿瘤坏死因子α和 CD68，一种巨噬细胞标志物，减少 35%至 65%，P < 0.0001），同时增加了抗炎细胞因子白细胞介素 10（~5 倍，P < 0.0001）。AdipoRon 还通过增加肌肉增殖和分化标志物的 2 倍来改善肌生成程序（与未治疗的 mdx 相比，P < 0.01 或更低）。血浆乳酸脱氢酶和肌酸激酶在 mdx-AR 小鼠中降低了 30-40%，反映出更少的肌膜损伤（P < 0.0001）。与未治疗的 mdx 小鼠相比，mdx-AR 小鼠的体力表现得到增强，肌肉力量和耐力均增加，在离心运动中跑步能力显著恢复。AdipoRon 主要通过增加 AMP 激活的蛋白激酶信号传导来激活 ApN 受体 1 发挥作用，这导致核因子-kappa B 的抑制、肌联蛋白（一种肌营养不良蛋白类似物）的上调以及向氧化和更具抵抗力的纤维表型的转变。AdipoRon 的作用随后在人类 DMD 肌管中得到重现。
这些结果表明，AdipoRon 对营养不良的肌肉有多种有益作用。这种分子为治疗 DMD 或其他肌肉和炎症疾病提供了有希望的治疗前景。
