Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA; King's College London British Heart Foundation Centre of Excellence, School of Cardiovascular Medicine & Sciences, London, United Kingdom.
Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA.
Free Radic Biol Med. 2023 Jan;194:23-32. doi: 10.1016/j.freeradbiomed.2022.11.025. Epub 2022 Nov 24.
Patients with heart failure with reduced ejection fraction (HFrEF) experience diaphragm weakness that contributes to the primary disease symptoms of fatigue, dyspnea, and exercise intolerance. Weakness in the diaphragm is related to excessive production of reactive oxygen species (ROS), but the exact source of ROS remains unknown. NAD(P)H Oxidases (Nox), particularly the Nox2 and 4 isoforms, are important sources of ROS within skeletal muscle that contribute to optimal cell function. There are reports of increased Nox activity in the diaphragm of patients and animal models of HFrEF, implicating these complexes as possible sources of diaphragm dysfunction in HFrEF. To investigate the role of these proteins on diaphragm weakness in HFrEF, we generated inducible skeletal muscle specific knockouts of Nox2 or Nox4 using the Cre-Lox system and assessed diaphragm function in a mouse model of HFrEF induced by myocardial infarction. Diaphragm maximal specific force measured in vitro was depressed by ∼20% with HFrEF. Skeletal muscle knockout of Nox4 provided full protection against the loss of maximal force (p < 0.01), while the knockout of Nox2 provided partial protection (7% depression, p < 0.01). Knockout of Nox2 from skeletal myofibers improved survival from 50 to 80% following myocardial infarction (p = 0.026). Our findings show an important role for skeletal muscle NAD(P)H Oxidases contributing to loss of diaphragm maximal force in HFrEF, along with systemic pathophysiological responses following myocardial infarction.
射血分数降低的心力衰竭（HFrEF）患者会出现膈肌无力的情况，这会导致疲劳、呼吸困难和运动不耐受等主要疾病症状。膈肌无力与活性氧（ROS）的过度产生有关，但 ROS 的确切来源尚不清楚。NAD(P)H 氧化酶（Nox），特别是 Nox2 和 4 同工型，是骨骼肌中 ROS 的重要来源，有助于细胞的最佳功能。有报道称，HFrEF 患者和动物模型的膈肌中 Nox 活性增加，这表明这些复合物可能是 HFrEF 中膈肌功能障碍的潜在来源。为了研究这些蛋白在 HFrEF 膈肌无力中的作用，我们使用 Cre-Lox 系统在诱导型骨骼肌特异性敲除 Nox2 或 Nox4 后，评估了心肌梗死诱导的 HFrEF 小鼠模型中的膈肌功能。体外测量的膈肌最大比力下降约 20%。骨骼肌敲除 Nox4 完全防止了最大力的丧失（p<0.01），而 Nox2 的敲除则提供了部分保护（7%的下降，p<0.01）。骨骼肌肌纤维中 Nox2 的敲除使心肌梗死后的存活率从 50%提高到 80%（p=0.026）。我们的研究结果表明，骨骼肌 NAD(P)H 氧化酶在 HFrEF 中导致膈肌最大力丧失以及心肌梗死后的全身病理生理反应中起着重要作用。
