PTEN inhibition improves muscle regeneration in mice fed a high-fat diet.
PTEN inhibition improves muscle regeneration in mice fed a high-fat diet.
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作者：
Hu Z;Wang H;Lee IH;Modi S;Wang X;Du J;Mitch WE
糖尿病损伤创面愈合的机制尚不清楚。为了确定机制，我们通过长期给小鼠喂高脂饮食(HFD)来诱导胰岛素抵抗。我们还研究了磷脂酰肌醇3，4，5-三磷酸(PIP3)在肌肉再生过程中的调节，因为增强的IGF-1信号可以促进肌肉再生。用心脏毒素损伤诱导肌肉再生，我们评估了喂饲HFD的小鼠的卫星细胞激活和肌肉成熟。我们还检测了PIP3及其调节酶、IRS-1相关的磷脂酰肌醇3-激酶(PI3K)和PTEN。利用肌肉的原代培养，我们研究了脂肪酸如何影响PTEN的表达，以及PTEN基因敲除如何影响肌肉生长。肌肉特异性PTEN基因敲除的小鼠被用来检测HFD如何改变肌肉再生。HFD增加了循环中的脂肪酸，损害了再生肌纤维的生长，延缓了肌纤维的成熟，增加了胶原的沉积。这些变化与肌祖细胞或卫星细胞的增殖受损无关，但主要与PTEN表达增加有关，PTEN的表达减少了肌肉中的PIP3。在培养的肌肉细胞中，棕榈酸酯直接刺激PTEN的表达并抑制细胞的生长。敲除PTEN基因可以恢复细胞生长。在小鼠中，肌肉特异性PTEN基因敲除改善了HFD诱导的肌肉修复缺陷。胰岛素抵抗通过阻止肌纤维成熟来损害肌肉再生。其机制涉及脂肪酸刺激的PTEN表达，从而降低肌肉PIP3。如果类似的途径发生在糖尿病患者身上，针对改善受损肌肉修复的治疗策略可能包括抑制PTEN活性。
Mechanisms impairing wound healing in diabetes are poorly understood. To identify mechanisms, we induced insulin resistance by chronically feeding mice a high-fat diet (HFD). We also examined the regulation of phosphatidylinositol 3,4,5-trisphosphate (PIP3) during muscle regeneration because augmented IGF-1 signaling can improve muscle regeneration. Muscle regeneration was induced by cardiotoxin injury, and we evaluated satellite cell activation and muscle maturation in HFD-fed mice. We also measured PIP3 and the enzymes regulating its level, IRS-1–associated phosphatidylinositol 3-kinase (PI3K) and PTEN. Using primary cultures of muscle, we examined how fatty acids affect PTEN expression and how PTEN knockout influences muscle growth. Mice with muscle-specific PTEN knockout were used to examine how the HFD changes muscle regeneration. The HFD raised circulating fatty acids and impaired the growth of regenerating myofibers while delaying myofiber maturation and increasing collagen deposition. These changes were independent of impaired proliferation of muscle progenitor or satellite cells but were principally related to increased expression of PTEN, which reduced PIP3 in muscle. In cultured muscle cells, palmitate directly stimulated PTEN expression and reduced cell growth. Knocking out PTEN restored cell growth. In mice, muscle-specific PTEN knockout improved the defects in muscle repair induced by HFD. Insulin resistance impairs muscle regeneration by preventing myofiber maturation. The mechanism involves fatty acid–stimulated PTEN expression, which lowers muscle PIP3. If similar pathways occur in diabetic patients, therapeutic strategies directed at improving the repair of damaged muscle could include suppression of PTEN activity.
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