Increases of M2a macrophages and fibrosis in aging muscle are influenced by bone marrow aging and negatively regulated by muscle-derived nitric oxide.
Increases of M2a macrophages and fibrosis in aging muscle are influenced by bone marrow aging and negatively regulated by muscle-derived nitric oxide.
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DOI：
10.1111/acel.12350
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发表时间：
2015-08
期刊：
影响因子：
7.8
通讯作者：
Tidball JG
中科院分区：
文献类型：
--
作者：
Wang Y;Wehling-Henricks M;Samengo G;Tidball JG
肌肉老化与髓样细胞表型的变化有关，髓样细胞表型的变化可能影响肌肉结构的年龄相关变化。我们测试了防止肌肉神经元一氧化氮合酶（nNOS）的年龄相关性减少是否会导致肌肉中髓样细胞的年龄相关性变化。我们的研究结果表明，肌肉老化与抗炎M2 a巨噬细胞的升高有关，这可能会增加肌肉纤维化。在小鼠中表达肌肉特异性nNOS转基因可防止M2 a巨噬细胞中与年龄相关的增加。转基因表达也减少了胶原蛋白的表达，减少了肌肉纤维化。nNOS转基因阻止了与年龄相关的肌纤维化酶-1的增加，但不影响TGFβ的表达，表明转基因可能通过抑制肌纤维化酶依赖性促纤维化途径来预防与年龄相关的肌纤维化。虽然老化的卫星细胞或纤维脂肪形成前体（FAP）细胞也促进纤维化，但转基因表达对调节这些细胞纤维化活性的关键信号分子的表达没有影响。最后，我们测试了M2 a巨噬细胞的增加和相关的纤维化增加是否可归因于髓系细胞的老化。将年轻的骨髓细胞（BMCs）移植到年轻或老年小鼠体内，8个月后收集肌肉。与年龄匹配的非移植对照组相比，接受年轻BMCs的年轻小鼠的肌肉对M2 a巨噬细胞数量或胶原蛋白积累没有影响。然而，接受年轻BMC的老年小鼠的肌肉显示出较少的M2 a巨噬细胞和较少的胶原积累。因此，衰老肌肉中M2 a巨噬细胞的年龄相关性增加和相关的肌肉纤维化部分由骨髓细胞的年龄决定。
Muscle aging is associated with changes in myeloid cell phenotype that may influence age-related changes in muscle structure. We tested whether preventing age-related reductions in muscle neuronal nitric oxide synthase (nNOS) would obviate age-related changes in myeloid cells in muscle. Our findings show that muscle aging is associated with elevations of anti-inflammatory M2a macrophages that can increase muscle fibrosis. Expression of a muscle-specific nNOS transgene in mice prevented age-related increases in M2a macrophages. Transgene expression also reduced expression of collagens and decreased muscle fibrosis. The nNOS transgene prevented age-related increases in arginase-1 but did not influence TGFβ expression, indicating that the transgene may prevent age-related muscle fibrosis by inhibiting the arginase-dependent profibrotic pathway. Although aged satellite cells or fibro-adipogenic precursor (FAPs) cells also promote fibrosis, transgene expression had no effect on the expression of key signaling molecules that regulate fibrogenic activity of those cells. Finally, we tested whether increases in M2a macrophages and the associated increase in fibrosis were attributable to aging of myeloid lineage cells. Young bone marrow cells (BMCs) were transplanted into young or old mice, and muscles were collected 8 months later. Muscles of young mice receiving young BMCs showed no effect on M2a macrophage number or collagen accumulation compared to age-matched, nontransplanted controls. However, muscles of old mice receiving young BMCs showed fewer M2a macrophages and less accumulation of collagen. Thus, the age-related increase in M2a macrophages in aging muscle and the associated muscle fibrosis are determined in part by the age of bone marrow cells.