Exogenous parathyroid hormone attenuates ovariectomy-induced skeletal muscle weakness in vivo
Exogenous parathyroid hormone attenuates ovariectomy-induced skeletal muscle weakness in vivo
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DOI：
10.1016/j.bone.2021.116029
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发表时间：
2021-06-11
期刊：
影响因子：
4.1
通讯作者：
Haro, Hirotaka
中科院分区：
文献类型：
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作者：
Fujimaki, Taro;Ando, Takashi;Haro, Hirotaka
骨质疏松症通常影响老年人，并与显著的发病率和死亡率有关。骨密度的丧失会导致肌肉萎缩，增加骨折的风险。然而，肌肉脂肪含量和液滴大小会因衰老和行动能力障碍而增加，与肌肉功能呈负相关，也是运动功能下降的原因之一。Teriparatide是人甲状旁腺激素(PTH)1-34的合成形式，已广泛用于治疗骨质疏松症。虽然甲状旁腺激素在体外对肌肉分化有积极的影响，但肌肉质量和能量保存的确切功能和机制仍不清楚，特别是在体内。在这项研究中，我们利用去卵巢的小鼠模型研究了甲状旁腺素对骨骼肌萎缩和功能障碍的影响。取8周龄雌性C57BL/6J小鼠，摘除卵巢或进行假手术。在每个手术组内，将小鼠分为PTH注射组和对照组。根据握力、跑步机跑步和乳酸浓度来评估运动功能。甲状旁腺素受体在骨骼肌细胞和成肌细胞中有表达。PTH可抑制去卵巢所致的骨丢失，但不能抑制子宫萎缩或体重增加；PTH不仅可消除去卵巢所致的握力和最大跑步速度的降低，而且显著降低去卵巢所致的乳酸浓度的升高(与赋形剂对照组相比)。甲状旁腺激素还可抑制卵巢切除引起的肌肉纤维氧化能力、横截面积和肌细胞内脂质含量的降低，并诱导细胞增殖、细胞迁移和肌肉分化，同时通过Wnt/β-catenin途径减少C2C12成肌细胞的脂质分泌。PTH显著改善去卵巢小鼠的肌肉无力和运动诱导的乳酸水平。我们的体外研究表明，PTH/Wnt信号调节成肌细胞的增殖、迁移和分化，并减少成肌细胞的脂质分泌。因此，甲状旁腺激素可以调节肌肉功能和生理的多个方面，并可能成为骨质疏松患者的一种新的治疗策略。
Osteoporosis commonly affects the elderly and is associated with significant morbidity and mortality. Loss of bone mineral density induces muscle atrophy and increases fracture risk. However, muscle lipid content and droplet size are increased by aging and mobility impairments, inversely correlated with muscle function, and a cause of reduced motor function. Teriparatide, the synthetic form of human parathyroid hormone (PTH) 1-34, has been widely used to treat osteoporosis. Although PTH positively affects muscle differentiation in vitro, the precise function and mechanisms of muscle mass and power preservation are still poorly understood, especially in vivo. In this study, we investigated the effect of PTH on skeletal muscle atrophy and dysfunction using an ovariectomized murine model. Eight-week-old female C57BL/6J mice were ovariectomized or sham-operated. Within each surgical group, the mice were divided into PTH injection or control subgroups. Motor function was evaluated based on grip strength, treadmill running, and lactic acid concentration. PTH receptor was expressed in skeletal muscle cells and myoblasts. PTH inhibited ovariectomy-induced bone loss but not uterine atrophy or increased body weight; PTH not only abolished ovariectomy-induced reduction in grip strength and maximum running speed, but also significantly reduced the ovariectomy-induced increase in lactic acid concentration (compared with that observed in the vehicle control). PTH also abrogated the ovariectomy-induced reduction in the oxidative capacity of muscle fibers, their cross-sectional area, and intramyocellular lipid content, and induced cell proliferation, cell migration, and muscle differentiation, while reducing lipid secretion by C2C12 myoblasts via the Wnt/beta-catenin pathway. PTH significantly ameliorated muscle weakness and attenuated exercise-induced lactate levels in ovariectomized mice. Our in vitro study demonstrated that PTH/Wnt signaling regulated the proliferation, migration, and differentiation of myoblasts and also reduced lipid secretion in myoblasts. Thus, PTH could regulate several aspects of muscle function and physiology, and may represent a novel therapeutic strategy for patients with osteoporosis.