Division of Plastic and Reconstructive Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard University, Boston, MA, 02115, USA.
Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard University, Boston, MA, 02114, USA.
Adv Biol (Weinh). 2023 Oct;7(10):e2200320. doi: 10.1002/adbi.202200320. Epub 2023 Mar 29.
Aging is associated with loss of skeletal muscle regeneration. Differentially regulated vascular endothelial growth factor (VEGF)A with aging may partially underlies this loss of regenerative capacity. To assess the role of VEGFA in muscle regeneration, young (12-14 weeks old) and old C57BL/6 mice (24,25 months old) are subjected to cryoinjury in the tibialis anterior (TA) muscle to induce muscle regeneration. The average cross-sectional area (CSA) of regenerating myofibers is 33% smaller in old as compared to young (p < 0.01) mice, which correlates with a two-fold loss of muscle VEGFA protein levels (p = 0.02). The capillary density in the TA is similar between the two groups. Young VEGF mice, with a 50% decrease in systemic VEGFA activity, exhibit a two-fold reduction in the average regenerating fiber CSA following cryoinjury (p < 0.01) in comparison to littermate controls. ML228, a hypoxia signaling activator known to increase VEGFA levels, augments muscle VEGFA levels and increases average CSA of regenerating fibers in both old mice (25% increase, p < 0.01) and VEGF (20% increase, p < 0.01) mice, but not in young or littermate controls. These results suggest that VEGFA may be a therapeutic target in age-related muscle loss.
衰老是与骨骼肌再生能力丧失相关的。随着年龄的增长，血管内皮生长因子（VEGF）A 的表达会发生差异调控，这可能是导致再生能力丧失的部分原因。为了评估 VEGFA 在肌肉再生中的作用，我们将年轻（12-14 周龄）和老年（24、25 月龄）C57BL/6 小鼠的比目鱼肌（TA）进行冷冻损伤，以诱导肌肉再生。与年轻（p<0.01）小鼠相比，老年小鼠再生肌纤维的平均横截面积（CSA）小 33%，这与肌肉 VEGFA 蛋白水平降低两倍（p=0.02）相关。两组间 TA 的毛细血管密度相似。与同龄对照相比，系统 VEGFA 活性降低 50%的 VEGF 敲低小鼠在冷冻损伤后再生纤维 CSA 的平均水平降低了两倍（p<0.01）。ML228 是一种已知可增加 VEGFA 水平的低氧信号激活剂，可增加老龄（25%，p<0.01）和 VEGF 敲低（20%，p<0.01）小鼠的肌肉 VEGFA 水平，并增加再生纤维的平均 CSA，但对年轻或同龄对照没有影响。这些结果表明，VEGFA 可能是与年龄相关的肌肉丢失的治疗靶点。
