Study at a Glance
Heart failure with preserved ejection fraction (HFpEF) remains a major therapeutic challenge, largely because patients often continue to experience disabling exercise intolerance despite near-normal left ventricular ejection fraction. The study by Vahle and colleagues provides mechanistic evidence that skeletal muscle dysfunction in HFpEF is linked to mitochondrial abnormalities and altered cardiolipin biology, and that the mitochondria-targeted peptide Elamipretide (SS-31) can partially reverse these defects in a rat model.
This is a preclinical study, not a clinical trial in patients. Nevertheless, it is clinically relevant because skeletal muscle impairment is increasingly recognized as a major contributor to reduced functional capacity in HFpEF, and because mitochondrial dysfunction is a plausible therapeutic target beyond conventional hemodynamic therapies.
Clinical Background and Unmet Need
HFpEF accounts for roughly half of all heart failure cases and is associated with substantial symptom burden, frequent hospitalizations, reduced quality of life, and high healthcare costs. Unlike heart failure with reduced ejection fraction, HFpEF has lacked therapies that reliably improve symptoms, exercise capacity, and hard outcomes across broad patient populations.
Exercise intolerance in HFpEF is multifactorial. Cardiac filling abnormalities, pulmonary vascular changes, impaired peripheral oxygen extraction, inflammation, and skeletal muscle abnormalities can all contribute. In recent years, peripheral mechanisms have gained attention, especially muscle deconditioning, reduced capillary density, fiber atrophy, altered calcium handling, and mitochondrial dysfunction. These abnormalities can lower oxidative capacity and limit the muscle’s ability to sustain activity.
Cardiolipin is a phospholipid located in the inner mitochondrial membrane that supports the structure and function of respiratory-chain complexes. When cardiolipin is depleted or structurally altered, mitochondrial respiration becomes less efficient, reactive oxygen species may increase, and energy production may suffer. Elamipretide is designed to target mitochondria and stabilize cardiolipin, thereby improving mitochondrial bioenergetics. The current study asked whether cardiolipin dysregulation is present in skeletal muscle in HFpEF and whether Elamipretide can improve muscle function through this mechanism.
Study Design
The investigators used female Zucker fatty spontaneously hypertensive heart failure F1 hybrid lean rats as controls (n=10) and obese rats as the HFpEF phenotype group (n=24). At 20 weeks of age, the HFpEF rats were randomized to receive either NaCl (n=12) or Elamipretide (n=12) for 12 weeks. Skeletal muscle was then analyzed using a broad experimental approach that included whole-muscle force testing, single-fiber mechanics, mitochondrial respiration assays, histology, and molecular analyses.
The study focused on mechanistic endpoints rather than survival or clinical events. Key outcomes included cardiolipin content and maturation, expression of tafazzin, contractile performance at the whole-muscle and single-fiber level, titin phosphorylation, fiber cross-sectional area, and markers of oxidative stress.
Key Findings
1) HFpEF skeletal muscle showed mitochondrial and structural impairment
Compared with lean controls, HFpEF rats had evidence of cardiolipin disruption in skeletal muscle. Total cardiolipin levels were reduced by 6.8% (P=0.007), and cardiolipin maturation was altered, as reflected by changes in tafazzin expression. Tafazzin is an enzyme involved in cardiolipin remodeling, and its altered expression supports the idea that mitochondrial membrane composition is disturbed in HFpEF muscle.
These rats also showed contractile dysfunction, titin hyperphosphorylation, fiber atrophy, and increased oxidative stress markers. Titin is a giant sarcomeric protein that contributes to passive stiffness and active force transmission in muscle; abnormal phosphorylation can alter mechanical properties and reduce efficiency. In practical terms, the muscle in HFpEF appeared both metabolically stressed and mechanically impaired.
2) Elamipretide improved whole-muscle force
Treatment with Elamipretide improved contractile function in both studied muscles. In the soleus, whole-muscle force increased by 8.2% (P=0.041), and in the extensor digitorum longus, force increased by 10.9% (P=0.016). Although these percentage changes may appear modest, even small improvements in force generation can be biologically meaningful in a model where muscle weakness contributes to reduced exercise tolerance.
The effect across both a slow-twitch muscle (soleus) and a more fast-twitch muscle (extensor digitorum longus) suggests that the benefit was not confined to a single fiber type. This strengthens the argument that mitochondrial stabilization may have broad peripheral effects.
3) Elamipretide improved single-fiber mechanics
At the single-fiber level, Elamipretide had an even more striking effect in the soleus, where contractile function improved by 173.2% (P<0.001). In the extensor digitorum longus, the improvement was 66.0%, although the reported significance was not statistically clear (P=ns). Single-fiber experiments are especially useful because they reduce confounding from connective tissue, perfusion, and neural inputs, suggesting that the therapeutic effect may be directly related to intrinsic muscle fiber function.
These findings indicate that the treatment improved the efficiency or quality of force generation at a cellular level, not merely the integrated performance of the whole muscle.
4) Elamipretide normalized titin phosphorylation and prevented atrophy
One of the more interesting mechanistic findings was the reduction in titin phosphorylation with treatment. In the soleus, titin phosphorylation decreased by 35.4% (P<0.001), and in the extensor digitorum longus by 40.2% (P<0.001). This suggests that the abnormal titin state seen in HFpEF muscle is at least partly reversible. Because titin regulates passive tension and contributes to sarcomeric integrity, normalization of its phosphorylation may improve muscle mechanics and resilience.
Elamipretide also prevented the development of muscle atrophy. Fiber size increased by 49% in the soleus (P=0.001) and 54.8% in the extensor digitorum longus (P<0.001) compared with untreated HFpEF animals. Preservation of muscle mass is clinically important because atrophy is a major contributor to weakness, fatigue, and functional limitation.
5) Mitochondrial function appeared to improve
The authors report improved mitochondrial function, presumably through cardiolipin-mediated improvements in oxidative phosphorylation. This is biologically plausible because cardiolipin helps organize respiratory complexes and supports efficient ATP production. Although the abstract does not provide a full quantitative breakdown of mitochondrial respiration parameters, the overall pattern fits a coherent mechanistic model: Elamipretide stabilizes the inner mitochondrial membrane, improves bioenergetics, lowers oxidative stress, and thereby supports better muscle function.
Interpretation and Mechanistic Insight
This study supports a peripheral, mitochondria-centered view of HFpEF symptom biology. Rather than focusing only on the heart, it highlights skeletal muscle as a target organ in which bioenergetic failure and structural remodeling may contribute directly to exercise intolerance.
The cardiolipin hypothesis is particularly attractive because it connects several observed abnormalities: reduced mitochondrial efficiency, oxidative stress, altered sarcomeric signaling, fiber atrophy, and reduced force generation. If cardiolipin integrity is compromised, mitochondrial membranes may become less effective at supporting oxidative phosphorylation. That can diminish ATP supply, increase reactive oxygen species, and potentially trigger downstream changes in protein phosphorylation and muscle remodeling.
Elamipretide is therefore not simply a symptomatic therapy; it is a mechanism-based intervention aimed at a fundamental cellular process. The study suggests that correcting mitochondrial membrane dysfunction can improve both structure and function in HFpEF skeletal muscle.
Strengths of the Study
Several features strengthen the work. First, the investigators used a clinically relevant HFpEF rat model that incorporates obesity and hypertension, two common human HFpEF features. Second, they examined both whole-muscle and single-fiber function, which provides a more complete physiological picture. Third, the study integrated functional, histologic, and molecular data, making the mechanistic narrative more convincing than any single assay alone.
In addition, the finding that Elamipretide affected multiple endpoints consistently, including force, titin phosphorylation, and muscle size, suggests a biologically coherent treatment effect rather than a chance finding isolated to one measurement.
Important Limitations
Despite its promise, the study has clear limitations. The most important is that it is preclinical, so the results cannot be assumed to translate directly to patients with HFpEF. Rat models capture only part of the human syndrome, and human HFpEF is highly heterogeneous, involving diverse phenotypes, comorbidities, and degrees of exercise limitation.
The sample size was modest, and the work was conducted in female animals only. That is relevant because HFpEF is more common in women, but sex-specific biology may also influence mitochondrial responses and limits generalizability to male patients. The treatment duration and endpoints were focused on physiology rather than clinical outcomes such as exercise capacity, symptoms, hospitalization, or survival.
Another limitation is that the abstract reports improved mitochondrial function “presumably” through cardiolipin-mediated oxidative phosphorylation, indicating that the causal chain is not fully proven. Additional studies are needed to confirm whether cardiolipin stabilization is the direct driver of improved muscle performance or one component of a broader mitochondrial effect.
Clinical Relevance and Future Directions
For clinicians, the most important message is not that Elamipretide is ready for routine HFpEF treatment, but that skeletal muscle mitochondrial dysfunction deserves more attention as a therapeutic target. Patients with HFpEF often report exertional fatigue out of proportion to resting cardiac measurements. A drug that improves muscle bioenergetics could, in principle, complement therapies that act on volume status, blood pressure, or neurohormonal pathways.
Future work should determine whether the preclinical benefits seen here translate into improved peak oxygen consumption, walking distance, fatigue scores, or quality of life in humans. It will also be important to identify which HFpEF phenotypes are most likely to respond. Patients with prominent obesity, insulin resistance, or marked exercise intolerance may be particularly relevant candidates for investigation.
Mechanistically, future studies should further map how cardiolipin remodeling, tafazzin activity, titin phosphorylation, oxidative stress, and mitochondrial respiration interact over time. Biomarkers that reflect mitochondrial membrane health could also help select patients and monitor response.
Conclusion
This study adds strong preclinical evidence that cardiolipin stabilization with Elamipretide can improve skeletal muscle performance in a HFpEF rat model. By enhancing mitochondrial function, reducing oxidative stress, normalizing titin phosphorylation, and preventing fiber atrophy, the intervention addresses several biologically relevant contributors to exercise intolerance.
While translation to patient care remains unproven, the work reinforces an important concept in HFpEF: symptoms are not only cardiac, but also peripheral and metabolic. If these findings are confirmed in human studies, mitochondrial-targeted therapy could become a meaningful addition to the HFpEF treatment landscape.
Funding and Clinical Trial Registration
The abstract provided does not list funding information or a clinicaltrials.gov registration number. As this was a preclinical animal study, clinical trial registration is not applicable unless a corresponding human study is conducted.
References
1. Vahle B, Weidner S, Tomalka A, Schauer A, Augstein A, Männel A, Barthel P, Friedrich J, Beck G, Labeit S, Bowen TS, Siebert T, Linke A, Adams V. Targeting Mitochondrial Dysfunction With Elamipretide (SS-31) Improves Skeletal Muscle Performance in a HFpEF Rat Model. Circulation. Heart failure. 2026-06-15:e014397. PMID: 42290373.
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4. Taegtmeyer H, Razeghi P, Hawthorne MH, et al. Metabolic remodeling and mitochondrial dysfunction in heart failure. Circ Res. 2016;118(8):1455-1468.
5. Dai DF, Hsieh EJ, Liu Y, et al. Mitochondrial proteome remodelling in pressure overload-induced heart failure. J Mol Cell Cardiol. 2012;55:83-90.
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Medical journal-style illustration of HFpEF skeletal muscle mitochondria being stabilized by Elamipretide, with visible cardiolipin membranes, enhanced ATP production, reduced oxidative stress, and improved muscle fiber contraction, clean clinical background, high-resolution, scientifically accurate, dramatic but professional lighting.
