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Neuromuscular Physiology
Published in Michael H. Stone, Timothy J. Suchomel, W. Guy Hornsby, John P. Wagle, Aaron J. Cunanan, Strength and Conditioning in Sports, 2023
Michael H. Stone, Timothy J. Suchomel, W. Guy Hornsby, John P. Wagle, Aaron J. Cunanan
Additional protein filaments primarily composed of titin (connectin) stabilize myosin myofilaments along the longitudinal axis. Titin is a large protein (3000 kD) that runs half the length of a sarcomere, essentially the length of the myosin myofilaments, and also attaches them to the Z-discs (91, 185). Titin also appears to stabilize and maintain myosin positioning within the middle of the sarcomere as well as stabilizing the entire sarcomere during both contraction and relaxation. Nebulin likely stabilizes actin in a similar manner. Titin is a molecular equivalent of a steel spring; both titin and nebulin likely contribute to the elastic properties of muscle (91, 127, 185). Differences in protein isoforms, particularly titin, may contribute to differences in strength, power (71, 126), and running economy (115) and may be related to training status. Skeletal muscle myosin-binding protein C (MyBP-C) is a myosin myofilament-associated protein (Figure 1.11c). It is localized in distinct regions (C-zones) of the sarcomere. MyBP-C activated by Ca++-sensitizes the actin myofilament and modulates actin myofilament velocity. At least two isoforms of MyBP-C (fast- and slow-type) are expressed in a fiber type specific manner (118).
Peripartum Cardiomyopathy and Heart Failure in Pregnancy
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Anita Saraf, Fred H. Rodriguez
Thus far, a single unifying hypothesis defining the origin of PPCM has not been identified. Multiple mechanisms have been suggested as possible driving factors in inducing PPCM and have been described comprehensively by Lindley et al25 and others.2,12,16,26–33 Given regional and familial clustering of PPCM, there is a clear genetic predisposition. Furthermore, there is a significant overlap between PPCM and idiopathic, dilated cardiomyopathy within family clusters, and, in these cases, mutations causing premature truncation of protein titin may be responsible.34 Other implicated mutations have involved proteins associated with titin, suggesting that functional disruption of titin within the cardiomyocyte may be central to the development of PPCM.35 However, titin-associated cardiomyopathies constitute only a small percentage of PPCM.34
Cancer and exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Tormod S. Nilsen, Pernille Hojman, Henning Wackerhage
Let us get specific about mutated cancer genes. In 2007 researchers published the results of sequencing the DNA of the 514 kinases in cancers and then compared the cancer DNA to normal DNA (15). Surprisingly, the gene with most mutations was TTN which encodes titin, a muscle protein. Titin is only expressed in skeletal muscle and the heart and probably almost never in cancer cells. Thus, even if the titin gene is mutated in cancer cells it will not have an effect because the titin protein will not be present. TTN mutations are thus typical passenger gene mutations.
Effect of nebivolol on altered skeletal and cardiac muscles induced by dyslipidemia in rats: impact on oxidative and inflammatory machineries
Published in Archives of Physiology and Biochemistry, 2022
Ghada Farouk Soliman, Omnia Mohamed Abdel-Maksoud, Mohamed Mansour Khalifa, Laila Ahmed Rashed, Walaa Ibrahim, Heba Morsi, Hanan Abdallah, Nermeen Bastawy
Reactive oxygen species (ROS) are important for the regulation of several body functions (Di Meo et al.2016). They are generated in skeletal muscles both during rest and contraction (Powers et al.2011). Mitochondria are major sources of ROS within the striated muscle cell (Görlach et al.2015). The skeletal muscles contain abundant antioxidant Defence system to protect against changes in the redox state. Data exist regarding the deleterious effects of oxidative stress within striated muscle tissues at several levels including cell membrane, sarcoplasmic reticulum, up to myofibrils (Powers et al.2011). Thin filament protein oxidation negatively affects contractile function in striated muscles by reducing calcium sensitivity of the myofilament (Lamb and Westerblad 2011, Steinberg 2013). Changes may occur in titin as a result of oxidative stress in striated muscles (Beckendorf and Linke 2015). Superoxide generated within striated muscle fibres causes oxidation of the ryanodine receptor and, thus, interferes with calcium release (Cherednichenko et al.2004, Xia et al.2003). Glutathione (GSH) is a hydrogen donor formed mainly in the liver, and its reduced form plays important roles in reducing H2O2 and some other cellular antioxidants (Powers et al.2011, Di Meo et al.2016). In addition to diminished expression of cardiac antioxidant enzymes with resultant oxidative stress by the effect of hypercholesterolaemia (Csonka et al.2016).
Vericiguat for the treatment of heart failure: mechanism of action and pharmacological properties compared with other emerging therapeutic options
Published in Expert Opinion on Pharmacotherapy, 2021
Jean-Sébastien Hulot, Jean-Noël Trochu, Erwan Donal, Michel Galinier, Damien Logeart, Pascal De Groote, Yves Juillière
sGC has a key role in generating cGMP [9] with sGC-derived production of cGMP being essential for normal cardiac and vascular function [10–12]. cGMP is indeed a key second messenger to mediate vaso- and cardiac relaxation. In HF, NO availability and functionality of sGC are impaired, resulting in an increased oxidative stress and loss of cGMP production. In other terms, the NO−sGC−cGMP pathway is impaired in HF which may contribute to the progression of cardiovascular disease (CVD) in terms of endothelial, myocardial and vascular dysfunction [11,13]. Notably, a deficiency in cGMP is common to both HFrEF and HFpEF [12]. Oxidative stress can also stimulate autophagy, apoptosis, or necrosis, leading to the loss of cardiomyocytes and their replacement with collagen, and to fibrosis [14,15]. Moreover, left-ventricular remodeling/stiffness is associated with hypophosphorylation of titin found in cardiomyocytes which is associated with an impaired cGMP-dependent protein kinase G (PKG) activity [16–18]. Titin is the third myofilament of the cardiac muscle [19]. By having direct and indirect links with several signaling molecules and having multiple phosphorylation sites in the Z-disk, M-band, and I-band (containing the N2B element) segments, titin is recognized as a major regulator of cardiomyocyte stiffness. For example, the level of phosphorylation of the N2B element, notably through PKG, regulates the myofibrillar stiffness [19].
Matrix metalloproteinase-12 cleaved fragment of titin as a predictor of functional capacity in patients with heart failure and preserved ejection fraction
Published in Scandinavian Cardiovascular Journal, 2021
Patricia Palau, Alexander Lynge Reese-Petersen, Eloy Domínguez, Jose María Ramón, Laura López, Anna Mollar, Francisco Javier Chorro, Juan Sanchis, Julio Núñez
Titin is an elastic myofilament protein found in cardiac sarcomere that is the dominant regulator of passive myocardial tension and an essential determinant of diastolic function of the heart [1,2]. Post-transcriptional and translational titin modifications have been implicated in the pathophysiology of heart failure with preserved ejection fraction (HFpEF) [3,4]. Theoretically, assays that could reliably measure fragments of degraded titin in serum could potentially be used in the assessment of myocardial damage/remodeling. Along this line, serum levels of matrix metalloproteinase-12 cleaved fragment of titin (TIM), a specific marker of degradation of cardiac titin by matrix metalloproteinase (MMP)-12 has been proposed as a potential cardiovascular biomarker [5]. Indeed, some authors reported increased titin proteolysis in human heart diseases associated with increased myocardial oxidative stress [6]. The clinical utility and prognostic performance of this marker in patients with HFpEF remain unknown. In this work, we aimed to evaluate the association between serum levels of TIM and maximal functional capacity assessed by the percentage of predicted peak exercise oxygen uptake (pp-peakVO2) in patients with HFpEF. Additionally, we aimed to evaluate the clinical factors related to TIM concentration and the relationship between TIM and the risk of adverse clinical events.