Skeletal muscle-specific Keap1 disruption modulates fatty acid utilization and enhances exercise capacity in female mice.
Skeletal muscle-specific Keap1 disruption modulates fatty acid utilization and enhances exercise capacity in female mice.
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DOI：
10.1016/j.redox.2021.101966
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发表时间：
2021-07
期刊：
影响因子：
11.4
通讯作者：
Motohashi H
中科院分区：
文献类型：
--
作者：
Onoki T;Izumi Y;Takahashi M;Murakami S;Matsumaru D;Ohta N;Wati SM;Hatanaka N;Katsuoka F;Okutsu M;Yabe Y;Hagiwara Y;Kanzaki M;Bamba T;Itoi E;Motohashi H
骨骼肌的健康对预防各种与年龄有关的疾病很重要。骨骼肌质量的减少，即所谓的肌肉减少症，是老年人身体残疾、生活质量差和慢性病的根本原因。转录因子NRF2在细胞抗氧化应激、代谢和线粒体活性调控中发挥重要作用。为了确定骨骼肌NRF2对运动能力的贡献，我们对NRF2的负调节因子KEAP1进行了骨骼肌特异性抑制，并检测了NRF2通路激活在骨骼肌中的细胞自主和非细胞自主作用。我们发现骨骼肌中NRF2的激活增加了雌性小鼠的慢氧化肌纤维类型，并提高了运动耐力。我们还观察到，骨骼肌中NRF2通路激活的雌性小鼠表现出增强的运动诱导的动员和脂肪酸β-氧化。这些结果表明，骨骼肌中NRF2的激活通过体液和/或神经元信号传导促进了与脂肪组织的通信，促进了脂肪酸作为能量来源的利用，从而增加了线粒体活性和运动时有效的能量产生，从而提高了运动耐力。系统敲低Keap1可增强小鼠的运动耐力。骨骼肌中Keap1缺失激活NRF2通路。骨骼肌缺乏Keap1可增强雌性小鼠的耐力。骨骼肌缺乏Keap1促进运动诱导的脂肪酸利用。
Skeletal muscle health is important for the prevention of various age-related diseases. The loss of skeletal muscle mass, which is known as sarcopenia, underlies physical disability, poor quality of life and chronic diseases in elderly people. The transcription factor NRF2 plays important roles in the regulation of the cellular defense against oxidative stress, as well as the metabolism and mitochondrial activity. To determine the contribution of skeletal muscle NRF2 to exercise capacity, we conducted skeletal muscle-specific inhibition of KEAP1, which is a negative regulator of NRF2, and examined the cell-autonomous and non-cell-autonomous effects of NRF2 pathway activation in skeletal muscles. We found that NRF2 activation in skeletal muscles increased slow oxidative muscle fiber type and improved exercise endurance capacity in female mice. We also observed that female mice with NRF2 pathway activation in their skeletal muscles exhibited enhanced exercise-induced mobilization and β-oxidation of fatty acids. These results indicate that NRF2 activation in skeletal muscles promotes communication with adipose tissues via humoral and/or neuronal signaling and facilitates the utilization of fatty acids as an energy source, resulting in increased mitochondrial activity and efficient energy production during exercise, which leads to improved exercise endurance. Systemic Keap1 knockdown enhances exercise endurance capacity in mice. Keap1 deficiency in skeletal muscle activates NRF2 pathway. Keap1 deficiency in skeletal muscle enhances endurance capacity in female mice. Keap1 deficiency in skeletal muscle promotes exercise-induced fatty acid utilization.
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影响因子：
7.3
作者：
Al-Sawaf, Othman;Fragoulis, Athanassios;Wruck, Christoph Jan
通讯作者：
Wruck, Christoph Jan
影响因子：
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Knatko EV;Tatham MH;Zhang Y;Castro C;Higgins M;Dayalan Naidu S;Leonardi C;de la Vega L;Honda T;Griffin JL;Hay RT;Dinkova-Kostova AT
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影响因子：
7.4
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影响因子：
5.2
作者：
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通讯作者：
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影响因子：
2.9
作者：
Katsuoka, Fumiki;Yokozawa, Junji;Yamamoto, Masayuki
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Yamamoto, Masayuki