Skeletal muscle contractile protein function is preserved in human heart failure

Okada, Yôko; Toth, Michael J.; VanBuren, Peter

doi:10.1152/japplphysiol.01072.2007

Cited by 17 publications

(19 citation statements)

References 40 publications

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“…One of the most frequently used ABPs for frictional loading experiments is alpha-actinin ((Bing et al 2000; Greenberg et al 2009b; Janson et al 1992; Malmqvist et al 2004; Okada et al 2008; Pant et al 2009; VanBuren et al 2002)). Typically, the index of retardation (the amount of alpha-actinin necessary to stop actin filament sliding velocity) is reported (Bing et al 2000).…”

Section: Resultsmentioning

confidence: 99%

The molecular basis of frictional loads in the in vitro motility assay with applications to the study of the loaded mechanochemistry of molecular motors

Greenberg

Moore

2010

Cytoskeleton

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Molecular motors convert chemical energy into mechanical movement, generating forces necessary to accomplish an array of cellular functions. Since molecular motors generate force, they typically work under loaded conditions where the motor mechanochemistry is altered by the presence of a load. Several biophysical techniques have been developed to study the loaded behavior and force generating capabilities of molecular motors yet most of these techniques require specialized equipment. The frictional loading assay is a modification to the in vitro motility assay that can be performed on a standard epifluorescence microscope, permitting the high-throughput measurement of the loaded mechanochemistry of molecular motors. Here, we describe a model for the molecular basis of the frictional loading assay by modeling the load as a series of either elastic or viscoelastic elements. The model, which calculates the frictional loads imposed by different binding proteins, permits the measurement of isotonic kinetics, force-velocity relationships, and power curves in the motility assay. We show computationally and experimentally that the frictional load imposed by alpha-actinin, the most widely employed actin binding protein in frictional loading experiments, behaves as a viscoelastic rather than purely elastic load. As a test of the model, we examined the frictional loading behavior of rabbit skeletal muscle myosin under normal and fatigue-like conditions using alpha-actinin as a load. We found that, consistent with fiber studies, fatigue-like conditions cause reductions in myosin isometric force, unloaded sliding velocity, maximal power output, and shift the load at which peak power output occurs. V C 2010 Wiley-Liss, Inc.Key Words: alpha-actinin, isotonic, force-velocity relationship, power, skeletal muscle fatigue Introduction T he myosin family of molecular motors is a diverse superfamily of actin binding proteins (ABP) that convert the energy from ATP hydrolysis into motion and force in order to accomplish an array of cellular functions [for review, see Sellers, 2000;O'Connell et al., 2007]. The in vitro motility assay is a useful tool for studying the molecular basis of myosin-based movement under a variety of well controlled experimental conditions Tyska and Warshaw, 2002]. This technique permits the study of myosin mechanics while at the same time, retaining many of the features of solution biochemistry. In the in vitro motility assay, myosin is bound to a cover glass surface and a solution containing fluorescently labeled actin filaments is applied to the myosin surface in the presence of ATP, allowing for the measurement of actin filament movement via fluorescence microscopy [Kron and Spudich, 1986]. The typical motility assay measures the sliding velocity of myosin in the absence of an exogenously added load, providing important information on the actomyosin contractile mechanism. Under physiological conditions, however, myosins typically operate against a load, making it desirable to study myosin force generation...

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Section: Resultsmentioning

confidence: 99%

The molecular basis of frictional loads in the in vitro motility assay with applications to the study of the loaded mechanochemistry of molecular motors

Greenberg

Moore

2010

Cytoskeleton

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“…Furthermore, patients with HF often develop reduced skeletal muscle function, manifesting itself as exercise intolerance [43,44]; and are often at risk for developing non-cardiac deficits, including skeletal muscle myopathies [45,46]. While some studies show that insults to the heart do not appear to alter skeletal muscle structure and function [47], other evidence suggests that cardiac myopathies do adversely affect skeletal muscle function in humans [48]. To further understand the relationship between heart failure and skeletal muscle function, we investigated whether DCM-induced HF in (t/t) mice altered the ultrastructure or function of the skeletal muscles, compared to the WT control.…”

Section: Discussionmentioning

confidence: 99%

Cardiac Myosin Binding Protein-C Plays No Regulatory Role in Skeletal Muscle Structure and Function

Lin

Govindan²,

Lee³

et al. 2013

PLoS ONE

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Myosin binding protein-C (MyBP-C) exists in three major isoforms: slow skeletal, fast skeletal, and cardiac. While cardiac MyBP-C (cMyBP-C) expression is restricted to the heart in the adult, it is transiently expressed in neonatal stages of some skeletal muscles. However, it is unclear whether this expression is necessary for the proper development and function of skeletal muscle. Our aim was to determine whether the absence of cMyBP-C alters the structure, function, or MyBP-C isoform expression in adult skeletal muscle using a cMyBP-C null mouse model (cMyBP-C(t/t)). Slow MyBP-C was expressed in both slow and fast skeletal muscles, whereas fast MyBP-C was mostly restricted to fast skeletal muscles. Expression of these isoforms was unaffected in skeletal muscle from cMyBP-C(t/t) mice. Slow and fast skeletal muscles in cMyBP-C(t/t) mice showed no histological or ultrastructural changes in comparison to the wild-type control. In addition, slow muscle twitch, tetanus tension, and susceptibility to injury were all similar to the wild-type controls. Interestingly, fMyBP-C expression was significantly increased in the cMyBP-C(t/t) hearts undergoing severe dilated cardiomyopathy, though this does not seem to prevent dysfunction. Additionally, expression of both slow and fast isoforms was increased in myopathic skeletal muscles. Our data demonstrate that i) MyBP-C isoforms are differentially regulated in both cardiac and skeletal muscles, ii) cMyBP-C is dispensable for the development of skeletal muscle with no functional or structural consequences in the adult myocyte, and iii) skeletal isoforms can transcomplement in the heart in the absence of cMyBP-C.

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“…Reduced isometric force and calcium-activated actomyosin ATPase activity in patients with HF may be due to a decline in density of contractile proteins and the specific rate of cross-bridge attachment or in both [28,30,52]. A reduction in contractile protein content appears to be the most likely explanation of reduced muscle strength since single-fiber muscle contractile protein function has been reported to unaltered in patients with HF [53]. …”

Section: Muscle Fiber Atrophy and Changes In Total Muscle Massmentioning

confidence: 99%

Metabolic and structural impairment of skeletal muscle in heart failure

Zizola

Schulze

2012

Heart Fail Rev

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Physiologic endurance exercise performance is primarily limited by cardiac function. In patients with heart failure, there is dissociation between cardiac performance and exercise capacity, suggesting a distinct role of abnormal peripheral organ function, including skeletal muscle function. The impact of heart failure upon skeletal muscle and exercise performance will be discussed with a focus on molecular, structural, and functional derangements in skeletal muscle of patients with heart failure. KeywordsSkeletal Muscle; Metabolism; Heart Failure Heart failure is defined as the inability of the heart to adequately perfuse peripheral tissues. The clinical syndrome of heart failure (HF) involves a complex interplay of skeletal muscle and peripheral vascular adaptations resulting from decreased myocardial performance. The classic symptoms of HF are exertional fatigue and dyspnea. It has traditionally been hypothesized that the major limitation to exercise performance results from a reduced cardiac output response to exercise, leading to skeletal muscle hypoperfusion and lactic acidosis [1]. However, secondary changes in other organ systems such as skeletal muscle, the vascular system, and the lungs play important roles in the genesis of fatigue and dyspnea [2].Though peak exercise capacity is clearly dependent on the cardiac output response to exercise, it is not the sole determinant of exercise performance in patients with HF since patients with similar reductions in left ventricular function have a wide range of exercise capacity. Furthermore, therapeutic interventions aimed at acutely increasing cardiac output such as inotropic drugs have limited impact on exercise capacity or peak VO 2 [3][4][5]. This discrepancy between enhanced cardiac output and fixed peak VO 2 can be explained on the basis of the peripheral vascular and skeletal muscle derangements in HF. Due to regional vascular or skeletal abnormalities the augmented cardiac output cannot be utilized by the exercising muscle beds and, therefore, peak VO 2 is not altered. Evidence for a peripheral abnormality in HF was first described in the 1970s by Zelis [6,7] .

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Skeletal muscle contractile protein function is preserved in human heart failure

Abstract: Okada Y, Toth MJ, VanBuren P. Skeletal muscle contractile protein function is preserved in human heart failure.

Cited by 17 publications

References 40 publications

The molecular basis of frictional loads in the in vitro motility assay with applications to the study of the loaded mechanochemistry of molecular motors

The molecular basis of frictional loads in the in vitro motility assay with applications to the study of the loaded mechanochemistry of molecular motors

Cardiac Myosin Binding Protein-C Plays No Regulatory Role in Skeletal Muscle Structure and Function

Metabolic and structural impairment of skeletal muscle in heart failure

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