How the Largest Protein in Humans Affects Heart Health & Diabetes

The giant sarcomere protein titin, the reason eccentric muscle contraction is stronger, is also a major determinant of cardiomyocyte stiffness and contributor to cardiac strain sensing. Titin-based forces are highly regulated in health and disease, which aids in the regulation of myocardial function, including cardiac filling and output. Due to the enormous size, complexity, and malleability of the titin molecule, titin properties are also vulnerable to dysregulation, as observed in various cardiac disorders. This review provides an overview of how cardiac titin properties can be changed at a molecular level, including the role isoform diversity and post-translational modifications (acetylation, oxidation, and phosphorylation) play in regulating myocardial stiffness and contractility. This article considers how the above regulation becomes unbalanced in heart disease, with an emphasis on changes in titin stiffness and protein quality control. In this context, new insights into the key pathologic mechanisms of human cardiomyopathy due to a truncation in the titin gene are discussed. Muscle Atrophy and Skeletal Muscle Myopathies Muscular atrophy occurs when the rate of muscle protein breakdown exceeds muscle protein synthesis. It is a predominant symptom of several pathologies including muscle myopathies or cardiac and cancer cachexia (Bonaldo and Sandri, 2013). A hallmark of muscle atrophy is a massive loss of skeletal muscle triggered by activation of the UPS and autophagy (Schiaffino et al., 2013). High muscle loss apparently includes increased sarcomere protein turnover. Lang et al. reported changes in titin ubiquitination, particularly within the C-terminal region, after sciatic nerve section in mouse gastrocnemius muscle, indicating elevated titin turnover during atrophy (Lang et al., 2017). Myofibrillar myopathies (MFMs) are characterized by histological alterations such as focal disintegration of myofibrils predominantly at the Z-disk and protein aggregation in myofibers (Kley et al., 2016). DM describes metabolic diseases that lead to elevated blood glucose levels due to a lack of insulin or a reduced effectiveness of insulin. The pathology of diabetes mellitus is associated with increased morbidity and mortality due to coronary artery disease, peripheral artery disease, stroke, cardiomyopathy and congestive heart failure (King et al., 1998; Plutzky, 2011). Reference: Titin (TTN): from molecule to modifications, mechanics, and medical significance. Cardiovascular Research (2022) 118, 2903–2918. https://doi.org/10.1093/cvr/cvab328 Want to learn more about muscle contraction, mitochondria, Metabolic energy, and the titin protein? Check out our online, board-certified and accredited continuing education courses here: https://intricateartseminars.com/course/muscle-metabolic-energy-courses/ Subscribe to my YouTube Channel here: https://www.youtube.com/channel/UC66zKmIQiuxoqOURh5MKNRQ?sub_confirmation=1