Abstract 15493: Akt1-Mediated Skeletal Muscle Growth Enhances Blood Flow Recovery After Hind Limb Ischemia by Activating Heme Oxygenase-1 in Macrophage
Background: Supervised exercise is established intervention for patients with peripheral artery disease (PAD). In addition to aerobic exercise, it has been recognized that resistance exercise has beneficial effects for these patients. However, underling mechanism by which growing muscle improves blood flow is unclear.
Hypothesis: Skeletal muscle growth enhances angiogenesis by modulating macrophage phenotype in ischemic lesion.
Methods: We utilized skeletal muscle-specific, inducible Akt1 transgenic (Akt1 TG) mice, that can lead to the growth of functional skeletal muscle. Skeletal muscle specific heme oxygenase-1 (HO-1) knockout mice were generated by crossing HO-1-Flox mice with ACTA1-Cre mice. These mice were subjected to unilateral femoral artery ligation to induce hind limb ischemia, and blood flow recovery was assessed by laser Doppler and immunohistochemistry. Adenovirus-mediated Akt1 overexpression experiments were performed in C2C12 myotubes.
Results: Blood flow recovery after hind limb ischemia was significantly increased in Akt1 TG mice than WT mice. Comprehensive proteomics analysis using skeletal muscle samples identified 7.4-folds upregulation of HO-1 in Akt1-TG mice. Immunohistochemistry for HO-1 in skeletal muscle section showed that the expression of HO-1 was not within muscle cells but in macrophages. Consistent with these findings, adenoviral-mediated overexpression of Akt1 did not increase HO-1 protein in C2C12 myotubes. In contrast, the conditioned medium from Akt1-overexpressed C2C12 myotubes increased HO-1 expression in macrophages, which was accompanied by increased arginase-1 and decreased TNF-α expression. In Akt1 TG mice, enhanced blood flow recovery and capillary density following hind limb ischemia was completely abolished by HO-1 inhibitor Tin-mesoporphyrin. On the other hand, blood flow recovery after hind limb ischemia was not different in between WT mice and skeletal muscle specific HO-1 knockout mice.
Conclusions: Akt1-mediated skeletal muscle growth improves blood flow recovery after hindlimb ischemia by enhancing HO-1 expression in macrophage. Our data support the concept that resistance training represents an alternative exercise intervention to the PAD patients.
Author Disclosures: Y. Onoue: None. Y. Izumiya: None. S. Hanatani: None. T. Ishida: None. S. Yamamura: None. Y. Kimura: None. S. Araki: None. S. Hokimoto: None.
- © 2016 by American Heart Association, Inc.