Highlights
Patients with heart failure with reduced ejection fraction (HFrEF) showed higher resting skeletal muscle myosin ATP consumption than matched controls, supporting the concept that peripheral muscle energetics are intrinsically abnormal in this syndrome.
Proteomics identified distinct regulation of acetyl-lysine sites in HFrEF skeletal muscle, suggesting that post-translational remodeling may contribute to altered contractile protein behavior and inefficient energy use.
Ex vivo exposure of isolated human myofibres to mavacamten produced a dose-dependent reduction in ATP consumption, reversing the excess energetic burden seen in HFrEF fibres.
The findings position skeletal muscle myosin dynamics as a potential therapeutic target, although the work remains preclinical and does not yet establish functional benefit, safety, or clinical efficacy in patients.
Background and Clinical Context
HFrEF remains a major cause of morbidity, hospitalization, and premature death worldwide. Although contemporary guideline-directed medical therapy has substantially improved survival, many patients continue to experience fatigue, reduced exercise capacity, and impaired quality of life despite optimized cardiac care. These symptoms are not explained solely by central hemodynamic failure. A substantial literature has shown that skeletal muscle in chronic heart failure undergoes structural, metabolic, and mitochondrial changes that contribute to exercise intolerance.
Peripheral abnormalities in HFrEF include reduced oxidative capacity, fiber type shifts, impaired perfusion, mitochondrial dysfunction, inflammation, and derangements in high-energy phosphate handling. These changes matter clinically because peak oxygen uptake, walking capacity, and fatigue burden often correlate only modestly with left ventricular ejection fraction. In other words, the skeletal muscle phenotype can become an important determinant of symptoms and functional status, independent of cardiac output alone.
Against this background, the present study addresses a more specific and less explored question: whether skeletal muscle myosin itself becomes energetically inefficient in HFrEF. Myosin ATPase activity is central to muscle energy expenditure because ATP hydrolysis powers cross-bridge cycling. If resting or near-resting myosin consumes ATP excessively in HFrEF, then reducing this biochemical drain could in principle improve energy economy. That idea has translational appeal, particularly because pharmacologic myosin inhibition is already clinically established in another setting: mavacamten is approved for symptomatic obstructive hypertrophic cardiomyopathy, where it reduces excessive cardiac myosin-actin interactions. Whether a related approach might beneficially modulate skeletal muscle energetics in heart failure is a novel question.
Study Design and Methods
Ansaldo and colleagues conducted an ex vivo mechanistic study using skeletal muscle tissue obtained from 11 patients with HFrEF and 10 controls matched for age, sex, and body mass index. The use of human tissue, rather than animal models alone, is a notable strength because it directly examines the disease substrate of interest. Individual myofibres were isolated and incubated with varying concentrations of mavacamten, a small-molecule myosin inhibitor.
The investigators assessed myosin ATP consumption using 2′-(or-3′)-O-(N-Methylanthraniloyl) adenosine 5′-triphosphate chase experiments. This fluorescence-based approach is designed to interrogate nucleotide turnover kinetics and thereby infer ATPase-related activity in myosin-containing fibres. In parallel, LC/MS-based proteomics profiling was performed to characterize molecular differences between HFrEF and control muscle, including post-translational modifications.
The abstract does not provide detailed information on muscle biopsy site, HFrEF etiology, medication profile, New York Heart Association class, left ventricular ejection fraction range, or prespecified statistical analysis plan. Likewise, no clinical endpoint, functional testing, or in vivo drug administration was involved. This is therefore best understood as a translational proof-of-concept study rather than a therapeutic efficacy trial.
Key Findings
Resting skeletal muscle energetics were abnormal in HFrEF
The central biological observation was that resting muscle fibres from patients with HFrEF displayed higher myosin energy consumption than fibres from controls. This suggests that skeletal muscle in HFrEF is not merely weaker or deconditioned, but may be metabolically inefficient at the molecular motor level. Such inefficiency could help explain why patients often report early fatigue and poor exertional tolerance even when resting symptoms are reasonably controlled.
This finding is particularly important because it shifts attention from mitochondrial ATP production alone to ATP demand. Much prior work in heart failure has focused on impaired energy supply, reduced oxidative phosphorylation, or altered phosphocreatine handling. By contrast, this study implicates excessive ATP consumption by the contractile apparatus itself. In clinical physiology terms, both inadequate supply and excessive demand can worsen energetic balance; targeting demand may therefore be therapeutically complementary.
Proteomic evidence suggested molecular remodeling of skeletal muscle myosin regulation
The investigators also observed distinct regulation of acetyl-lysine sites in HFrEF skeletal muscle. Although the abstract does not enumerate the specific proteins or residues involved, lysine acetylation is a biologically meaningful post-translational modification that can alter protein conformation, enzymatic function, intermolecular interactions, and stability. In muscle, such changes may plausibly influence myosin head state transitions, ATP turnover behavior, or sarcomeric regulation.
The mechanistic implication is that HFrEF-associated skeletal muscle dysfunction may involve biochemical remodeling of contractile proteins, not just atrophy or changes in fibre composition. This aligns with the broader concept that chronic heart failure produces a systemic myopathy with metabolic and signaling abnormalities. It also raises the possibility that acetylation-related pathways could become future biomarkers or drug targets, although that remains speculative at present.
Mavacamten reduced ATP consumption in a dose-dependent manner
When HFrEF myofibres were exposed ex vivo to mavacamten, myosin ATP consumption fell in a dose-dependent fashion. Importantly, the reduction was sufficient to reverse the pathological over-consumption observed in patient fibres. Dose-response behavior strengthens causal inference because it suggests a pharmacologic effect rather than random fluctuation.
This result is the translational core of the paper. It indicates that an existing myosin-directed compound can directly modulate skeletal muscle energy use in diseased human tissue. The authors interpret this as relief of the energetic burden in HFrEF skeletal muscle. Conceptually, if excessive ATP usage at rest or low workload contributes to fatigue and impaired reserve, then normalizing that expenditure could improve energy availability for activity. However, that clinical extrapolation remains unproven.
What the study did not show
The abstract reports no patient-level functional outcomes such as peak VO2, 6-minute walk distance, fatigue scores, muscle strength, or quality of life. No safety data are available for skeletal-muscle targeting because the drug was not administered systemically to participants. There are also no quantitative effect sizes, confidence intervals, or P values provided in the abstract. As a result, the findings should be interpreted as biologically provocative rather than practice changing.
Mechanistic Interpretation
Myosin molecules can occupy conformational states with different ATP turnover rates. In cardiac muscle, mavacamten stabilizes an energy-sparing state and reduces the number of myosin heads available for productive actin interaction, thereby decreasing hypercontractility. A parallel skeletal muscle mechanism is plausible, though not yet fully established. If HFrEF skeletal myosin is biased toward a higher-turnover state, then mavacamten may shift the equilibrium toward a more energy-conserving conformation.
This idea fits with a broader model of peripheral dysfunction in HFrEF. Chronic neurohormonal activation, inflammation, oxidative stress, underperfusion, inactivity, and altered metabolic signaling may remodel the skeletal sarcomere and its regulatory environment. Post-translational changes such as lysine acetylation could contribute to this maladaptive state. In that context, myosin ATPase inhibition may act as a metabolic brake, reducing basal energy waste rather than simply depressing contractility.
That distinction matters. A therapy that merely weakens skeletal muscle would be undesirable in a population already prone to frailty and exercise limitation. A therapy that selectively reduces nonproductive or excessive ATP consumption while preserving needed force generation would be much more attractive. The present study does not yet resolve where mavacamten falls on that spectrum in vivo.
Clinical Relevance
For clinicians, the paper is most important as a reminder that HFrEF is a multisystem syndrome. Persistent symptoms despite optimized hemodynamic therapy may partly reflect peripheral muscle disease. The study advances a novel therapeutic concept: skeletal muscle energy demand modulation. If validated in vivo, this approach could complement exercise training, cardiac rehabilitation, iron repletion where indicated, and guideline-directed pharmacotherapy.
At the same time, any enthusiasm must be tempered by several practical concerns. Mavacamten is a cardiac-active drug with known effects on contractility in the approved hypertrophic cardiomyopathy setting. Extrapolating to HFrEF is not straightforward, because excessive myocardial depression would be a serious risk in a population with reduced systolic function. Even if skeletal muscle benefits were real, systemic administration might produce unacceptable cardiac effects unless dose, tissue selectivity, or drug design could be optimized. A future path might involve skeletal-muscle-selective myosin modulators or delivery strategies rather than repurposing current dosing paradigms.
Another relevant clinical question is whether reducing resting ATP consumption translates into better physical performance. Resting energetic economy is valuable, but exercise capacity depends on integrated cardiovascular reserve, perfusion, mitochondrial oxidative function, neuromuscular recruitment, and ventilatory efficiency. Thus, molecular rescue at the fibre level may be necessary but not sufficient for meaningful symptomatic improvement.
Strengths and Limitations
Strengths
The study uses human skeletal muscle samples from patients with HFrEF, improving disease relevance compared with purely preclinical models. The experimental design links a mechanistic readout, ATP consumption, to a pharmacologic intervention with a plausible target. The addition of proteomics provides molecular context and opens the door to hypothesis generation about how HFrEF remodels the contractile apparatus.
Limitations
The sample size was small, with 11 HFrEF patients and 10 controls, which is reasonable for an intensive mechanistic tissue study but limits precision and subgroup analysis. The ex vivo design cannot replicate neurohormonal signaling, circulation, physical activity, drug metabolism, or whole-organism adaptation. Clinical heterogeneity is also an important issue; without detailed phenotyping, it is difficult to know whether the observed phenotype is consistent across ischemic and nonischemic HFrEF, across sex, or across varying disease severity.
Most importantly, the study does not establish that myosin ATPase inhibition improves function, symptoms, or outcomes. It also does not fully address whether lowering ATP consumption might impair force generation or worsen exercise performance under some conditions. Finally, because the publication date is recent and the abstract is concise, additional methodological details, effect estimates, and full supplemental data will be needed for a mature appraisal.
How This Fits With Existing Evidence
Current heart failure guidelines emphasize quadruple foundational therapy for HFrEF, device therapy when appropriate, and exercise rehabilitation, but they do not include targeted pharmacologic treatment of skeletal muscle energetics. This is largely because no such therapy has yet demonstrated clinical benefit. Nevertheless, peripheral skeletal muscle abnormalities are well recognized contributors to exercise intolerance in chronic heart failure.
Prior work has documented impaired mitochondrial density and function, reduced oxidative enzymes, abnormal muscle reflexes, and altered fibre composition in heart failure. Exercise training can partially reverse some of these abnormalities and remains one of the few interventions with consistent beneficial effects on functional capacity. The present study extends that field by pointing to myosin ATP turnover as another potentially actionable component of the peripheral phenotype.
It is also noteworthy that mavacamten has primarily been developed within cardiovascular medicine for myocardial sarcomere modulation, not skeletal muscle energetics. This study therefore illustrates the growing translational value of sarcomere biology across organ systems. Whether this becomes therapeutically feasible in HFrEF will depend on careful pharmacology and on demonstration that skeletal muscle benefits can be separated from undesirable cardiac effects.
Implications for Research
Several next steps follow naturally from this work. First, the findings should be replicated in larger, clinically well-characterized HFrEF cohorts with attention to sex, age, disease severity, and comorbidities such as diabetes, cachexia, and chronic kidney disease. Second, full proteomic mapping is needed to define which acetyl-lysine changes are most relevant and whether they correlate with ATP over-consumption.
Third, studies should determine whether ATP-sparing effects preserve or compromise force production and fatigue resistance under physiological contraction conditions. Fourth, animal and early-phase human studies will be needed to address systemic pharmacokinetics, tissue selectivity, and cardiac safety. Finally, any translational program must prioritize outcomes meaningful to patients, including exercise capacity, symptom burden, physical activity, and health status.
An especially important question is whether this strategy would complement exercise training or instead blunt adaptive skeletal muscle responses. Since exercise rehabilitation remains central to improving peripheral function in HFrEF, drug-based metabolic modulation should ideally augment, not substitute for, physical conditioning.
Conclusion
This study provides compelling early evidence that skeletal muscle myosin in HFrEF is energetically dysregulated and that ex vivo myosin ATPase inhibition with mavacamten can normalize excessive ATP consumption in patient myofibres. The work is mechanistically elegant and clinically provocative because it reframes skeletal muscle in HFrEF as a direct pharmacologic target rather than merely a downstream victim of low cardiac output.
However, the findings should remain in the translational domain for now. The study does not show clinical efficacy, and systemic use of a cardiac-active myosin inhibitor in HFrEF raises obvious safety considerations. Even so, the paper opens an important avenue of investigation: reducing peripheral energy waste as a strategy to improve the functional syndrome of heart failure. For clinicians and researchers interested in exercise intolerance, fatigue, and the systemic biology of HFrEF, this is a notable and hypothesis-generating contribution.
Funding and ClinicalTrials.gov
Funding information and a ClinicalTrials.gov registration number were not provided in the abstract or citation details supplied here. Readers should consult the full published article for funding disclosures, conflicts of interest, and any additional protocol information.
References
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