Langone Francesca, Cannata Stefano, Fuoco Claudia, Lettieri Barbato Daniele, Testa Stefano, Nardozza Aurelio Pio, Ciriolo Maria Rosa, Castagnoli Luisa, Gargioli Cesare, Cesareni Gianni
Department of Biology, University of Rome Tor Vergata, Rome, Italy.
Department of Biology, University of Rome Tor Vergata, Rome, Italy; Fondazione Santa Lucia Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy.
PLoS One. 2014 Dec 2;9(12):e114018. doi: 10.1371/journal.pone.0114018. eCollection 2014.
The skeletal muscle tissue has a remarkable capacity to regenerate upon injury. Recent studies have suggested that this regenerative process is improved when AMPK is activated. In the muscle of young and old mice a low calorie diet, which activates AMPK, markedly enhances muscle regeneration. Remarkably, intraperitoneal injection of AICAR, an AMPK agonist, improves the structural integrity of muscles of dystrophin-deficient mdx mice. Building on these observations we asked whether metformin, a powerful anti-hyperglycemic drug, which indirectly activates AMPK, affects the response of skeletal muscle to damage. In our conditions, metformin treatment did not significantly influence muscle regeneration. On the other hand we observed that the muscles of metformin treated mice are more resilient to cardiotoxin injury displaying lesser muscle damage. Accordingly myotubes, originated in vitro from differentiated C2C12 myoblast cell line, become more resistant to cardiotoxin damage after pre-incubation with metformin. Our results indicate that metformin limits cardiotoxin damage by protecting myotubes from necrosis. Although the details of the molecular mechanisms underlying the protective effect remain to be elucidated, we report a correlation between the ability of metformin to promote resistance to damage and its capacity to counteract the increment of intracellular calcium levels induced by cardiotoxin treatment. Since increased cytoplasmic calcium concentrations characterize additional muscle pathological conditions, including dystrophies, metformin treatment could prove a valuable strategy to ameliorate the conditions of patients affected by dystrophies.
骨骼肌组织在受伤后具有显著的再生能力。最近的研究表明，当AMPK被激活时，这种再生过程会得到改善。在年轻和年老小鼠的肌肉中，激活AMPK的低热量饮食能显著增强肌肉再生。值得注意的是，腹腔注射AICAR（一种AMPK激动剂）可改善肌营养不良蛋白缺陷的mdx小鼠肌肉的结构完整性。基于这些观察结果，我们询问二甲双胍（一种强大的抗高血糖药物，可间接激活AMPK）是否会影响骨骼肌对损伤的反应。在我们的实验条件下，二甲双胍治疗并未显著影响肌肉再生。另一方面，我们观察到，接受二甲双胍治疗的小鼠的肌肉对心脏毒素损伤更具弹性，肌肉损伤较小。因此，源自分化的C2C12成肌细胞系的体外肌管在与二甲双胍预孵育后对心脏毒素损伤更具抗性。我们的结果表明，二甲双胍通过保护肌管免于坏死来限制心脏毒素损伤。尽管这种保护作用背后的分子机制细节仍有待阐明，但我们报告了二甲双胍促进抗损伤能力与其抵消心脏毒素治疗诱导的细胞内钙水平升高能力之间的相关性。由于细胞质钙浓度升高是包括营养不良在内的其他肌肉病理状况的特征，二甲双胍治疗可能被证明是改善受营养不良影响患者状况的一种有价值的策略。
