Calcium sensitivity and muscle disease

Muscles contract when an action potential triggers the release of intracellular calcium which binds to troponin and allows crossbridge cycling and force production. It has long been known that some physiological interventions, such as adrenaline in the heart and acidosis in skeletal muscle, have substantial effects on the sensitivity of troponin to calcium which contribute to their physiological profile. In the cardiovascular field, drugs which increase cardiac calcium sensitivity have been in clinical use for at least 25 years and have achieved a modest role in the treatment of heart failure (Pollesello et al. 2016). In the last decade a class of drugs which selectively increase the calcium sensitivity of skeletal muscle has been developed and has triggered considerable interest in their potential for treatment of neuromuscular diseases (Russell et al. 2012). In ageing humans and many diseases, for instance heart failure and cancer, force production by muscle is reduced and fatigue during normal daily activities can become incapacitating. The hope is that this class of drugs might ameliorate these symptoms in a wide range of diseases. A new study by Cheng et al. (2019) explores some of these ideas in detail and encourages the idea that these drugs might have a role in the treatment of ischaemic limb diseases. They used a drug, CK-2066260, that has previously been shown to selectively increase the calcium sensitivity of skeletal troponin by slowing the dissociation rate of calcium from troponin (Hwee et al. 2017). Consequently this drug increases the force produced by muscle at intermediate stimulus frequencies, when the intracellular calcium is below saturation, while having no effect on intracellular calcium levels or force at high stimulus frequencies when the calcium levels are saturating. Energy consumption by muscle is principally associated with crossbridge cycling but a significant proportion is caused by the ATP consumed by the sarcoplasmic reticulum pump. As a consequence, in the presence of the drug, the same force can be achieved with a lower stimulus frequency and a lower intracellular calcium concentration and therefore the expenditure of energy in recycling calcium is reduced. Muscle fatigue is thought to be a situation in which the metabolic products of energy consumption cause reduced force production; the authors therefore predicted that this class of drugs would slow the rate of muscle fatigue. This prediction is amply confirmed by a clear series of experiments on isolated single fibres; for instance when muscles were fatigued at similar force levels, the rate of fatigue was approximately halved in the presence of the drug. Furthermore, measurements of the decline of ATP and glycogen confirmed that both energy stores declined more slowly in the presence of the drug. These improvements in muscle performance were confirmed in intact animals tested on a rotarod and uphill treadmill running. Of greater interest from a therapeutic perspective is the performance of the drug in a well-established model of peripheral ischaemia produced by tying the femoral artery, which reduces blood flow in the leg. Immediately after ligation, muscle fatigue produced by nerve stimulation of an intact, perfused leg muscle was slowed by CK-2066260. When both arteries were ligated and the animals allowed to recover, treadmill running was prolonged in the treated animals. While these animal experiments seem clear cut, translation of these approaches to humans has proved equivocal to date. For instance tirasemtiv, a first generation version of this class of drugs, has been evaluated in humans with claudication of leg caused by peripheral artery disease (Bauer et al. 2014). A single dose was given in a randomised, double blinded study which compared placebo and three drug concentrations. One outcome, the number of heel raises performed before pain or weakness intervened, showed significant improvement but not at all time points or in a dose-dependent manner. A second outcome, distance completed in a 6 min walk, was worsened by the presence of the drug. A feature of the studies of tirasemtiv is a substantial incidence of side-effects, particularly dizziness, euphoria, fatigue and gait disturbances, and it is likely that these side-effects contributed to the deterioration in the 6 min walk. Tirasemtiv has also been evaluated for the treatment of amyotrophic lateral sclerosis, a neurodegenerative disease causing progressive weakness and death due to respiratory failure typically 3–5 years after diagnosis (Shefner et al. 2019). This was a randomised, double-blind trial with placebo and three drug levels evaluated after 24 weeks. The primary end point was the decline of vital capacity (which depends in part on muscle strength) but this was not significantly affected by the drug. A notable feature of the trial was the dropout rate of 34% in the treated group again pointing to the substantial side-effect profile of the drug. Of those who tolerated the drug, there was a trend (P = 0.11) towards a dose-related reduction in the decline of vital capacity. The disappointing results of the clinical trials to date highlights the poor predictability of animal experiments for the treatment of human diseases. These drugs are only expected to increase force to the extent that muscles are submaximally activated and the improvement is limited by the absolute capacity of the muscle, which may be severely impacted by disease. A second generation drug with a reduced side-effect profile has now been tested in healthy humans (Andrews et al. 2018) and we await with interest a definitive clinical trial to determine the value of this class of drugs in human disease. None declared. Sole author. None.