Solaro R John, Goldspink Paul H, Wolska Beata M
Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL 60612, USA.
Department of Medicine, Section of Cardiology, University of Illinois at Chicago, Chicago, IL 60612, USA.
Biomedicines. 2024 May 2;12(5):999. doi: 10.3390/biomedicines12050999.
Novel therapies for the treatment of familial dilated cardiomyopathy (DCM) are lacking. Shaping research directions to clinical needs is critical. Triggers for the progression of the disorder commonly occur due to specific gene variants that affect the production of sarcomeric/cytoskeletal proteins. Generally, these variants cause a decrease in tension by the myofilaments, resulting in signaling abnormalities within the micro-environment, which over time result in structural and functional maladaptations, leading to heart failure (HF). Current concepts support the hypothesis that the mutant sarcomere proteins induce a causal depression in the tension-time integral (TTI) of linear preparations of cardiac muscle. However, molecular mechanisms underlying tension generation particularly concerning mutant proteins and their impact on sarcomere molecular signaling are currently controversial. Thus, there is a need for clarification as to how mutant proteins affect sarcomere molecular signaling in the etiology and progression of DCM. A main topic in this controversy is the control of the number of tension-generating myosin heads reacting with the thin filament. One line of investigation proposes that this number is determined by changes in the ratio of myosin heads in a sequestered super-relaxed state (SRX) or in a disordered relaxed state (DRX) poised for force generation upon the Ca activation of the thin filament. Contrasting evidence from nanometer-micrometer-scale X-ray diffraction in intact trabeculae indicates that the SRX/DRX states may have a lesser role. Instead, the proposal is that myosin heads are in a basal OFF state in relaxation then transfer to an ON state through a mechano-sensing mechanism induced during early thin filament activation and increasing thick filament strain. Recent evidence about the modulation of these mechanisms by protein phosphorylation has also introduced a need for reconsidering the control of tension. We discuss these mechanisms that lead to different ideas related to how tension is disturbed by levels of mutant sarcomere proteins linked to the expression of gene variants in the complex landscape of DCM. Resolving the various mechanisms and incorporating them into a unified concept is crucial for gaining a comprehensive understanding of DCM. This deeper understanding is not only important for diagnosis and treatment strategies with small molecules, but also for understanding the reciprocal signaling processes that occur between cardiac myocytes and their micro-environment. By unraveling these complexities, we can pave the way for improved therapeutic interventions for managing DCM.
目前缺乏治疗家族性扩张型心肌病（DCM）的新型疗法。根据临床需求确定研究方向至关重要。该疾病进展的触发因素通常是由于影响肌节/细胞骨架蛋白产生的特定基因变异。一般来说，这些变异会导致肌丝产生的张力降低，进而导致微环境内的信号异常，随着时间的推移会导致结构和功能适应不良，最终导致心力衰竭（HF）。目前的观点支持这样一种假说，即突变的肌节蛋白会导致心肌线性标本的张力-时间积分（TTI）出现因果性降低。然而，目前关于张力产生的分子机制，尤其是关于突变蛋白及其对肌节分子信号传导的影响，仍存在争议。因此，有必要弄清楚突变蛋白在DCM的病因和进展中是如何影响肌节分子信号传导的。这场争议的一个主要话题是控制与细肌丝反应的产生张力的肌球蛋白头部数量。一项研究表明，这个数量是由处于隔离超松弛状态（SRX）或无序松弛状态（DRX）的肌球蛋白头部比例的变化决定的，在细肌丝的钙激活后，这些状态随时准备产生力量。来自完整小梁的纳米-微米级X射线衍射的对比证据表明，SRX/DRX状态的作用可能较小。相反，有人提出，肌球蛋白头部在松弛时处于基础关闭状态，然后通过在细肌丝早期激活和粗肌丝应变增加过程中诱导的机械传感机制转变为开启状态。最近关于蛋白质磷酸化对这些机制的调节的证据也表明有必要重新考虑张力的控制。我们将讨论这些机制，这些机制导致了与在DCM复杂情况下与基因变异表达相关的突变肌节蛋白水平如何干扰张力相关的不同观点。解决各种机制并将它们纳入一个统一的概念对于全面理解DCM至关重要。这种更深入的理解不仅对于小分子诊断和治疗策略很重要，而且对于理解心肌细胞与其微环境之间发生的相互信号传导过程也很重要。通过揭示这些复杂性，我们可以为改善DCM的治疗干预铺平道路。
