Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Division of Vascular and Endovascular Surgery, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Division of Vascular Imaging and Intervention, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
J Surg Res. 2014 Aug;190(2):683-91. doi: 10.1016/j.jss.2014.01.020. Epub 2014 Jan 17.
Obesity is a major risk factor for the development of diabetes. Limb ischemia-reperfusion injury (IR) is a common clinical problem in diabetics who have compromised lower extremity perfusion. This study compared the histologic, metabolic, and functional outcomes after hind limb IR in diet-induced obese (DIO) and non-diabetic (ND) mice during the acute and the regenerative phases of IR.
DIO and ND mice were subjected to 1.5 h unilateral hind limb ischemia followed by 1- or 28-d IR. Muscle morphology, metabolic, and genomic stress were evaluated at days 1 and 28 IR; Acute inflammation and thrombosis were only measured at day-1 IR. At day 28, IR, skeletal muscle contractility, and maturation were also assessed.
At day-1 IR, similar levels of acute muscle fiber necrosis were seen in both groups. DIO mice demonstrated substantially greater inflammatory, prothrombotic, and genomic stress responses, which were also associated with a greater reduction in energy substrates and Akt phosphorylation. At 28d, there was no difference in the peak forces generated in the hind limbs for the two groups. DIO mice had reduced fatigue resistance compared with ND and larger areas of fat accumulation although there was no significant difference in muscle fiber maturation.
DIO mice had an exacerbated acute response to IR with enhanced metabolic deficit, fat accumulation, and defective functional recovery during the regenerative phase of IR. These changes in fatigue resistance reflect compromised functional recovery after IR injury and have relevance for the functional recovery of patients with metabolic syndrome and insulin resistance.
肥胖是糖尿病发展的一个主要危险因素。肢体缺血再灌注损伤（IR）是糖尿病患者下肢灌注受损的常见临床问题。本研究比较了饮食诱导肥胖（DIO）和非糖尿病（ND）小鼠在 IR 的急性和再生阶段后后肢 IR 后的组织学、代谢和功能结果。
DIO 和 ND 小鼠接受 1.5 小时单侧后肢缺血，然后进行 1 或 28 天 IR。在 IR 的第 1 天和第 28 天评估肌肉形态、代谢和基因组应激；仅在第-1 天 IR 时测量急性炎症和血栓形成。在第 28 天，还评估了 IR、骨骼肌收缩性和成熟度。
在第 1 天 IR 时，两组的急性肌纤维坏死程度相似。DIO 小鼠表现出更大的炎症、促血栓形成和基因组应激反应，这也与能量底物和 Akt 磷酸化的更大减少有关。在 28 天时，两组后肢产生的峰值力没有差异。与 ND 相比，DIO 小鼠的疲劳抵抗力降低，脂肪堆积更多，尽管肌肉纤维成熟度没有显著差异。
DIO 小鼠对 IR 的急性反应加剧，代谢缺陷增加，脂肪堆积增加，IR 的再生阶段功能恢复受损。疲劳抵抗力的这些变化反映了 IR 损伤后功能恢复受损，与代谢综合征和胰岛素抵抗患者的功能恢复有关。
