Preclinical characterization of the JAK/STAT inhibitor SGI-1252 on skeletal muscle function, morphology, and satellite cell content

Background
Recent studies have highlighted the JAK/STAT signaling pathway in the regulation of muscle satellite cell behavior. Herein we report preclinical studies designed to characterize the effects of a novel JAK/STAT inhibitor on plantar flexor skeletal muscle function, morphology, and satellite cell content.
Methods
The compound, SGI-1252, was administered orally (400mg/kg) in a 10% dextrose solution to wild type mice (n = 6) 3 times per week for 8 weeks. A control group (n = 6) received only the dextrose solution.
Results
SGI-1252 was well tolerated, as animals displayed similar weight gain over the 8-week treatment period. Following treatment, fatigue in the gastrocnemius-soleus-plantaris complex was greater in the SGI-1252 mice during a 300 second tetanic contraction bout (p = 0.035), though both the rate of fatigue and maximal force production were similar. SGI-1252 treated mice had increased type II myofiber cross-sectional area (1434.8 ± 225.4 vs 1754.7 ± 138.5 μm2), along with an increase in wet muscle mass (125.45 ± 5.46 vs 139.6 ± 12.34 mg, p = 0.032) of the gastrocnemius relative to vehicle treated mice. SGI-1252 treatment reduced gastrocnemius STAT3 phosphorylation 53% (94.79 ± 45.9 vs 44.5 ± 6.1 MFI) and significantly increased the concentration of Pax7+ satellite cells (2589.2 ± 105.5 vs 2859.4 ± 177.5 SC/mm3) in the gastrocnemius. SGI-1252 treatment suppressed MyoD (p = 0.013) and Myogenin (p<0.0001) expression in human primary myoblasts, resulting in reduced myogenic differentiation (p = 0.039).
Conclusions
Orally delivered SGI-1252 was well tolerated, attenuates skeletal muscle STAT3 activity, and increases satellite cell content in mouse gastrocnemius muscle, likely by inhibiting myogenic progression.

背景
近期研究已证实JAK/STAT信号通路（JAK/STAT signaling pathway）对肌肉卫星细胞（muscle satellite cell）行为具有调控作用。本研究开展临床前实验，旨在表征新型JAK/STAT抑制剂对跖屈骨骼肌功能、形态及卫星细胞含量的影响。

方法
本研究采用10%葡萄糖溶液配制化合物SGI-1252，以400mg/kg的剂量对野生型小鼠（n=6）经口灌胃给药，每周3次，持续8周；对照组（n=6）仅给予同等剂量的葡萄糖溶液。

结果
SGI-1252的耐受性良好，受试小鼠在8周给药周期内的体重增长与对照组无显著差异。给药结束后，在300秒强直收缩实验中，SGI-1252给药组小鼠的腓肠肌-比目鱼肌-跖肌复合体疲劳程度显著更高（p=0.035），但两组的疲劳速率与最大产力无明显差异。相较于溶剂对照组小鼠，SGI-1252给药组小鼠的腓肠肌Ⅱ型肌纤维横截面积显著升高（1434.8±225.4 vs 1754.7±138.5 μm²），腓肠肌湿重亦有所增加（125.45±5.46 vs 139.6±12.34 mg，p=0.032）。SGI-1252给药可使腓肠肌的STAT3磷酸化水平降低53%（94.79±45.9 vs 44.5±6.1 MFI），同时显著升高腓肠肌内Pax7阳性卫星细胞的密度（2589.2±105.5 vs 2859.4±177.5 SC/mm³）。此外，SGI-1252可抑制人原代肌母细胞中肌分化因子1（MyoD）与肌细胞生成素（Myogenin）的表达，进而降低成肌分化能力（p=0.039）。

结论
经口给药的SGI-1252耐受性良好，可抑制骨骼肌STAT3活性，并增加小鼠腓肠肌内的卫星细胞含量，其作用机制可能与阻断成肌进程相关。