Functional Consequences of Sarcomeric Protein Abnormalities in Failing Myocardium

Abstract

Sarcomeric protein abnormalities have been recognized for many years in heart failure due to dilated cardiomyopathy (DCM). In contrast, virtually nothing is known about myofilament abnormalities in heart failure occurring in association with diastolic dysfunction. With the exception of sarcomeric protein mutations that cause DCM, the most important mechanism of myofilament dysfunction in DCM is probably altered post-translational modification, in particular the phosphorylation state of troponins I and T and possibly myosin light chain. Other modifications, including oxidation and glycation, may also play a role. Myosin heavy chain isoform switching occurs in human heart failure, but its functional significance is uncertain. Myofilament abnormalities contribute significantly to myocardial dysfunction in DCM, although their relative importance compared with abnormal calcium handling is debated. One consistent functional abnormality in DCM is increased myofilament calcium sensitivity of tension generation, which contributes to slowed or incomplete relaxation. More recently, decreases in the optimal frequency of myofilament work and power generation have been recognized. These changes may contribute to depression of the force-frequency relation in DCM. Altered mechanoenergetics constitute one of the most important manifestations of myofilament dysfunction in heart failure. DCM and hemodynamic overload are associated with more economical and efficient energy utilization by the contractile machinery, which may be protective of the myocardium. This change is strongly associated with depressed myofibrillar ATPase activity. We speculate that the effectiveness of mechanical therapies such as resynchronization may at least in part be related to improved mechanical function without loss of this mechanoenergetic advantage.

RETRACTED: Angiotensin receptor blockade improves the net balance of cardiac Ca2+ handling-related proteins in sympathetic hyperactivity-induced heart failure

“…Over the last decades, several studies have shown that ventricular dysfunction is related to changes in phosphorylation status of sarco/ endoplasmic proteins (LeWinter, 2005;Paulino et al, 2010), reduced sarcoplasmic reticulum Ca 2+ ATPase (SERCA2) function (Pogwizd et al, 2001), upregulation of Na + -Ca 2+ exchanger (NCX) (Pogwizd and Bers, 2002) and diastolic Ca 2+ leak via ryanodine receptors (Ai et al, 2005). We have reported that Ca 2+ handling impairment is associated with ventricular dysfunction and HF progression Medeiros et al, 2008), where both pharmacological (Bartholomeu et al, 2008) and non-pharmacological (Vanzelli et al, 2010) therapies improved cardiac function by minimizing Ca 2+ transient abnormalities.…”

Changes in myofilament proteins, but not Ca2+ regulation, are associated with a high-fat diet-induced improvement in contractile function in heart failure

“…A MHC isoform switch is a key determinant of shortening velocity (which is primarily due to the intrinsic ATPase activity of fast ␣-MHC compared with slower ␤-MHC); this isoform shift translates to a decrease in contractility (44) and myocyte power output (13) and has been well documented in HF (21,25,40,45). The increased expression of MHC-␤ in the HFNC group could account for the decreased cell shortening velocity observed in isolated cardiomyocytes.…”

“…Likewise, the phosphorylation of other myofilament proteins, e.g., myosin-binding protein C (MyBP-C), troponin I, and myosin regulatory light chain (MRLC), have also been shown to alter Ca 2ϩ sensitivity and/or cross-bridge kinetics, impacting both in vitro and in vivo contractility (31,39). Alterations in the ratio of MHC isoforms and the phosphorylation status of other myofilament proteins have been implicated in the contractile dysfunction characteristic of HF in a variety of animal models (21,25,31,39,40). However, the mechanism(s) by which dietary lipids impact the Ca 2ϩ regulation of contractile function and myofilament protein composition in HF has not been investigated.…”

Exercise training improves the net balance of cardiac Ca2+ handling protein expression in heart failure

“…In contrast, recent studies have shown that exercise training increases stroke volume and, hence, cardiac output in patients with HF (7,9). Ventricular function is highly coupled with Ca 2ϩ transients in the heart, and myocardial dysfunction observed in severe HF is caused mainly by alterations in phosphorylation status of sarcomeric proteins (19) and a diminished sarcoplasmic reticulum Ca 2ϩ load that arises from enhanced activity and expression of Na ϩ -Ca 2ϩ exchanger (41), reduced sarcoplasmic reticulum Ca 2ϩ ATPase (SERCA2) function (32), and increased diastolic Ca 2ϩ leak via ryanodine receptors (1,22). In addition, alterations of SERCA2 activity have been attributed to a phosphorylatable protein, phospholamban (PLN) (8,13), which in its dephosphorylated form decreases the apparent Ca 2ϩ affinity of SERCA2.…”