Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, UAE.
Int J Mol Sci. 2020 Dec 22;22(1):37. doi: 10.3390/ijms22010037.
Sarcopenia has a significant negative impact on healthspan in the elderly and effective pharmacologic interventions remain elusive. We have previously demonstrated that sarcopenia is associated with reduced activity of the sarcoplasmic reticulum Ca ATPase (SERCA) pump. We asked whether restoring SERCA activity using pharmacologic activation in aging mice could mitigate the sarcopenia phenotype. We treated 16-month male C57BL/6J mice with vehicle or CDN1163, an allosteric SERCA activator, for 10 months. At 26 months, maximal SERCA activity was reduced 41% in gastrocnemius muscle in vehicle-treated mice but maintained in old CDN1163 treated mice. Reductions in gastrocnemius mass (9%) and in vitro specific force generation in extensor digitorum longus muscle (11%) in 26 versus 16-month-old wild-type mice were also reversed by CDN1163. CDN1163 administered by intra-peritoneal injection also prevented the increase in mitochondrial ROS production in gastrocnemius muscles of aged mice. Transcriptomic analysis revealed that these effects are at least in part mediated by enhanced cellular energetics by activation of PGC1-α, UCP1, HSF1, and APMK and increased regenerative capacity by suppression of MEF2C and p38 MAPK signaling. Together, these exciting findings are the first to support that pharmacological targeting of SERCA can be an effective therapy to counter age-related muscle dysfunction.
肌肉减少症对老年人的健康寿命有重大负面影响，而有效的药物干预措施仍难以实现。我们之前已经证明，肌肉减少症与肌浆网 Ca2+-ATP 酶（SERCA）泵的活性降低有关。我们想知道，在衰老的小鼠中使用药物激活来恢复 SERCA 活性是否可以减轻肌肉减少症表型。我们用载体或 CDN1163（一种别构 SERCA 激活剂）治疗 16 个月大的雄性 C57BL/6J 小鼠 10 个月。在 26 个月时，与对照组相比，载体处理的小鼠的比目鱼肌中最大 SERCA 活性降低了 41%，但老年 CDN1163 处理的小鼠中保持不变。26 个月龄与 16 个月龄野生型小鼠相比，比目鱼肌质量减少了 9%，伸趾长肌体外特定力生成减少了 11%，这些变化也被 CDN1163 逆转。腹腔注射 CDN1163 还可防止老年小鼠比目鱼肌中线粒体 ROS 产生增加。转录组分析表明，这些作用至少部分是通过激活 PGC1-α、UCP1、HSF1 和 APMK 增强细胞能量代谢，以及通过抑制 MEF2C 和 p38 MAPK 信号转导来增加再生能力来介导的。这些令人兴奋的发现首次支持，SERCA 的药物靶向治疗可能是一种有效的对抗与年龄相关的肌肉功能障碍的疗法。
