Abstract：
Sarcopenia and frailty are urgent socio-economic problems worldwide. Here we demonstrate a functional connection between the lateral hypothalamus (LH) and skeletal muscle through Slc12a8, a recently identified nicotinamide mononucleotide transporter, and its relationship to sarcopenia and frailty. Slc12a8-expressing cells are mainly localized in the LH. LH-specific knockdown of Slc12a8 in young mice decreases activity-dependent energy and carbohydrate expenditure and skeletal muscle functions, including muscle mass, muscle force, intramuscular glycolysis, and protein synthesis. LH-specific Slc12a8 knockdown also decreases sympathetic nerve signals at neuromuscular junctions and β2-adrenergic receptors in skeletal muscle, indicating the importance of the LH-sympathetic nerve-β2-adrenergic receptor axis. LH-specific overexpression of Slc12a8 in aged mice significantly ameliorates age-associated decreases in energy expenditure and skeletal muscle functions. Our results highlight an important role of Slc12a8 in the LH for regulation of whole-body metabolism and skeletal muscle functions and provide insights into the pathogenesis of sarcopenia and frailty during aging.
摘要：
肌肉减少症和虚弱是全球紧迫的社会经济问题。在这里，我们通过Slc12a8（最近发现的烟酰胺单核苷酸转运蛋白）证明了下丘脑外侧（LH）和骨骼肌之间的功能联系，以及它与肌少症和虚弱的关系。Slc12a8表达细胞主要位于LH中。在年轻小鼠中Slc12a8的LH特异性敲除降低了活动依赖性能量和碳水化合物支出以及骨骼肌功能，包括肌肉质量，肌肉力量,肌内糖酵解，和蛋白质合成。LH特异性Slc12a8敲低也会降低骨骼肌中神经肌肉接头和β2-肾上腺素能受体的交感神经信号，表明LH-交感神经-β2-肾上腺素能受体轴的重要性。Slc12a8在老年小鼠中的LH特异性过表达显着改善了与年龄相关的能量消耗和骨骼肌功能的降低。我们的结果强调了Slc12a8在LH中对调节全身代谢和骨骼肌功能的重要作用，并为衰老过程中肌肉减少症和虚弱的发病机理提供了见解。
