When fat meets the engine: implications of dietary rumenic acid on myosin‐targeting therapies in heart failure

Acute heart failure is associated with high morbidity and mortality, along with an increasing incidence of hospital admission worldwide. Traditional therapeutic agents, including phosphodiesterase inhibitors and/or catecholamines, acutely improve myocardial function but at the expense of increases in cardiac oxygen utilization and predisposition to life-threatening arrhythmias via alterations of cellular calcium (Maack et al. 2018). Recent treatment strategies viamyosinmodulation, such as the selective myosin effector omecamtiv mecarbil (Morgan et al. 2010), efficiently increase contractile function without impacting upon cellular calcium dynamics or activation of the adrenergic system. In genetic cardiomyopathies, such as hypertrophic cardiomyopathy (HCM), a disease characterized by hypercontractility and myocardial energetic depletion, viable treatment strategies are still lacking. While metabolic drugs, including perhexiline, have been shown to modestly improve the symptoms of patients, those agents are characterized by a pleiotropic action (George et al. 2016). The small-molecule myosin deactivator mavacamten reverses the hypercontractility, maladaptive cardiac remodelling, myofibrillar disarray and fibrosis in a mouse model of HCM (Green et al. 2016). Because of their selective binding to myosin, myosin-targeting agents may evolve as promising alternatives for treatment of cardiomyopathy and heart failure patients. In this issue of The Journal of Physiology, Pertici and co-workers investigated the impact of the trans fat rumenic acid on actomyosin function (Pertici et al. 2021). Low-load experiments with reconstituted motility assays show that rumenic acid (1) increases myosin release rates of phosphate and (2) calcium-sensitivity. Under loaded conditions in demembranated rat trabeculae, rumenic acid (3) decreased force generation. The authors identified similar modulation by rumenic acid on non-muscle myosin, while skeletal and smooth muscle myosin activity was unaffected. Using in silicomodelling, Pertici and co-workers estimated that rumenic acid binding to cardiac myosin occurs in an allosteric pocket formed by residues from the upper and lower 50K domains and the converter region (Pertici et al. 2021). The findings are important for two reasons: (a) mechanistically, this study validates this region of myosin as the hot-spot for de novo design of small-molecule therapeutics (e.g. mavacamten, omecamtiv mercabil, etc.), but (b) secondly, and perhaps the most important, Pertici et al. speculate that physiological concentrations of rumenic acid (≤5 μM) are likely sufficient to compete against pharmacological myosin modulators for the binding to cardiac myosin (Pertici et al. 2021). Hence, the overall success of any future clinical trial using small-molecule myosin modulators will require the close monitoring of dietary intake of rumenic acids (and potentially other acids) of participants during test trials. Naturally produced trans fats are produced in the rumen of ruminants (biohydrogenation) and are chemically characterized by having the trans double bond typically positioned at the delta ( )-11 position (e.g. rumenic acid [C18:2 cis9, trans11]). Natural trans fats differ considerably from their artificial counterparts, which are industrially produced (from partial hydrogenation of vegetable fat), in that industrial-derived trans-fatty acids have their double bonds in the -8,-9/-10,-ll/ and -12 positions (Gunstone, Harwood, & Dijkstra 2007). Past studies showed the trans -9 and -10 positions to be notoriously damaging to the human body, since they appear unable to undergo proper β-oxidation (likely caused by the artificial double bond positioning, a requirement to be recognized by mitochondrial desaturase enzymes). Dietary intake of industrially produced trans fats associates well with several cardiovascular risk factors and comorbidities. However, mechanistic research and information regarding trans-fatty acids produced from natural origin is still lacking. The study from Pertici and co-workers is the first to indicate that physiological concentrations of rumenic acid are sufficient to interfere with cardiac myosin, thereby reducing cellular force generation, and potentially myocardial function (Pertici et al. 2021). During myofilament contraction, myosin transits between three functional states. The (1) actin-bound state, which has a rapid ATP turnover, and two unbound states with very low ATP turnover: (2) the disorder relaxed state (DRX) with about 100-fold less activity than the actin-bound state, and (3) the super-relaxed state (SRX), which exhibits an additional 10-fold decrease in activity compared with the DRX state (Anderson et al. 2018). Actin-free myosin motors are in a dynamic DRX:SRX state equilibriumwith up to 60%ofmyosin heads held ‘in reserve’ in the energy-conserving SRX state. Destabilization of the SRX state and with it increased ATP turnover has been proposed to be causative of HCM. The latter is supported by the positive effects of mavacamten to reverse the HCM phenotype due to its primary effects in stabilizing the SRX state with consequent reduction in energetic load on the myocardium (Anderson et al. 2018). Less clear at this point is the mode of action of omecamtiv mecarbil on cardiac myosin. Although commonly described as a myosin activator that acts by increasing the fraction of actin-bound myosin motors with rapid ATP turnover, omecamtiv mecarbil inhibits basal ATP turnover ofmyosin as well (Malik et al. 2011). In combination with X-ray crystallographic data (Planelles-Herrero et al. 2017), this provides support for the concept that omecamtiv mecarbil can additionally stabilize an SRX-like state of myosin (Anderson et al. 2018). Notably, Pertici et al. show that rumenic acid, like mavacamten and omecamtiv, binds to the same region of the myosin motor