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  • Review Article
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Targeting the sarcomere to correct muscle function

Nature Reviews Drug Discovery volume 14, pages 313–328 (2015)Cite this article

Subjects

Key Points

  • The sarcomere is the most basic contractile unit in skeletal and cardiac muscle. Mutations in genes encoding sarcomeric proteins give rise to heritable myopathies, although muscle function is more commonly compromised by acquired neuromuscular or cardiac disease.

  • Sarcomeric modulators act on sarcomeric proteins to promote contraction or relaxation either by direct binding to specific sarcomeric proteins or by modulating signalling pathways.

  • Some phosphodiesterase 3 (PDE3) inhibitors increase cardiac contractility by acting as calcium mobilizers or calcium sensitizers, although the mechanisms underlying this difference are currently unclear. All PDE3 inhibitors are associated with arrhythmias and hypotension as side effects.

  • Myosin is the molecular motor that drives muscle contraction. Omecamtiv mecarbil (developed by Cytokinetics) is the first cardiac myosin activator to be tested in clinical trials for the treatment of heart failure with reduced ejection fraction.

  • The troponin complex switches muscle contraction on and off in response to calcium. There are several calcium-sensitizing compounds that act on the fast skeletal isoforms of troponin C and troponin I, which are currently in clinical and preclinical testing.

Abstract

Various human diseases can disrupt the balance between muscle contraction and relaxation. Sarcomeric modulators can be used to readjust this balance either indirectly by intervening in signalling pathways or directly through interaction with the muscle proteins that control contraction. Such agents represent a novel approach to treating any condition in which striated muscle function is compromised, including heart failure, cardiomyopathies, skeletal myopathies and a wide range of neuromuscular conditions. Here, we review agents that modulate the mechanical function of the sarcomere, focusing on emerging compounds that target myosin or the troponin complex.

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Figure 1: Basic structure of the sarcomere.
Figure 2: The multi-domain structure of myosin as it relates to the actin–myosin crossbridging cycle.
Figure 3: Three-dimensional structure of the regulatory N-terminal domain of cardiac troponin C.

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Acknowledgements

The authors' work is supported by Heart and Stroke Foundation of Canada, grant-in-aid G-14-0005884, and the Canadian Institutes of Health Research, operating grant 37769.

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  1. Division of General Internal Medicine, Department of Medicine, Faculty of Medicine and Dentistry, Clinical Sciences Building, University of Alberta, 11350 83 Avenue, Edmonton, T6G 2G3, Alberta, Canada

    Peter M. Hwang

  2. Department of Biochemistry, Faculty of Medicine and Dentistry, 474 Medical Sciences Building, University of Alberta, Edmonton, T6G 2H7, Alberta, Canada

    Brian D. Sykes

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B.D.S. has previously received a research grant from Cytokinetics for conducting structural biology studies.

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Glossary

Amyotrophic lateral sclerosis

(ALS). A neurodegenerative condition that leads to progressive loss of both upper and lower motor neurons.

Heart failure

The end stage of almost all heart disease, in which the heart is unable to pump sufficient blood to satisfy the metabolic needs of the body. Diagnosed by clinical signs and symptoms such as shortness of breath, elevated central venous pressure, and peripheral and pulmonary oedema.

Ejection fraction

The percent volume of blood ejected by the heart during systole; 60% or greater in healthy individuals, with a lower value (<45%) indicative of systolic dysfunction. Many medications have been shown to improve mortality in patients with a low ejection fraction.

Arrhythmias

Disturbances in the electrical conduction pathways of the heart causing abnormally fast or slow heart rate or inefficient contractions.

Hypotension

Low blood pressure that can lead to impaired perfusion of vital organs.

Positive inotropes

Compounds that increase the contractility of the heart to increase cardiac output.

K d

Drug Kd (dissociation constant) is the concentration at which 50% activity is achieved.

Peripheral vascular disease

A condition characterized by severe narrowing of arteries, typically in the legs, and is classically associated with smoking and diabetes. Impaired perfusion causes pain that is worsened with exertion and can progress to non-healing ulcers and amputation.

pCa50

The negative logarithm of the calcium concentration at which 50% activity is achieved.

Myasthenia gravis

An autoimmune disease that targets postsynaptic acetylcholine receptors of the neuromuscular junction, causing muscle weakness characterized by easy fatigability.

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Hwang, P., Sykes, B. Targeting the sarcomere to correct muscle function. Nat Rev Drug Discov 14, 313–328 (2015). https://doi.org/10.1038/nrd4554

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