Highlight
Heart failure with preserved ejection fraction (HFpEF) is increasingly recognized as a syndrome of impaired exercise tolerance, not simply a disorder of diastolic filling. In this rat study, the mitochondria-targeted peptide elamipretide improved skeletal muscle contractile performance, reduced titin hyperphosphorylation, and prevented muscle atrophy. The findings support cardiolipin stabilization as a biologically plausible strategy for HFpEF-related skeletal muscle dysfunction.
The work is important because it shifts attention beyond the myocardium and toward peripheral skeletal muscle, which is a major contributor to exertional limitation in HFpEF. However, the evidence remains preclinical, and clinical translation will require confirmation in human studies.
Clinical background and unmet need
HFpEF accounts for a large and growing proportion of heart failure cases, particularly among older adults and patients with obesity, hypertension, diabetes, and metabolic syndrome. Despite substantial morbidity, effective disease-modifying therapies remain limited. Many patients continue to report severe dyspnea, fatigue, and poor exercise capacity even when left ventricular ejection fraction is preserved.
Exercise intolerance in HFpEF is multifactorial. Cardiac stiffness and impaired filling contribute, but peripheral factors are increasingly appreciated. Among these, skeletal muscle abnormalities, reduced oxidative capacity, altered fiber composition, and mitochondrial dysfunction appear to play central roles. These abnormalities can limit oxygen utilization and muscular force generation during activity, thereby worsening functional status even when resting cardiac parameters are relatively stable.
Mitochondria are especially relevant because they supply energy for muscle contraction through oxidative phosphorylation. A key structural phospholipid in the inner mitochondrial membrane is cardiolipin, which helps organize respiratory chain complexes and maintain efficient ATP production. When cardiolipin integrity is disrupted, mitochondrial energetics decline, reactive oxygen species may increase, and contractile tissues can become less efficient. Prior work has suggested cardiolipin abnormalities in the myocardium of HFpEF, raising the possibility that similar changes occur in skeletal muscle and may be therapeutically targetable.
Elamipretide, also known as SS-31, is a mitochondria-targeted peptide that binds cardiolipin and is intended to stabilize inner mitochondrial membrane structure and improve respiratory chain function. This study asked whether cardiolipin dysregulation is present in HFpEF skeletal muscle and whether elamipretide can improve muscle performance in a relevant animal model.
Study design
This was a preclinical randomized intervention study in female Zucker fatty spontaneously hypertensive heart failure F1 hybrid lean and obese rats, a model used to recapitulate key HFpEF features such as obesity, hypertension, and exercise intolerance. Ten lean rats served as controls. Twenty-four obese rats with the HFpEF phenotype were randomized at 20 weeks of age to receive either NaCl (n=12) or elamipretide (n=12) for 12 weeks.
After treatment, investigators collected skeletal muscle tissue for multiple endpoints, including whole-muscle force, single-fiber mechanics, mitochondrial respiration, histology, and molecular analyses. The study also assessed cardiolipin content and maturation, including tafazzin expression, along with markers of oxidative stress and titin phosphorylation. Titin is a giant sarcomeric protein that contributes to passive and active muscle mechanics; abnormal phosphorylation can alter muscle stiffness and contractile behavior.
Primary mechanistic question
The central hypothesis was that HFpEF skeletal muscle would show cardiolipin dysregulation and that elamipretide would improve mitochondrial and contractile function by stabilizing cardiolipin and restoring oxidative phosphorylation.
Key findings
Compared with lean controls, HFpEF rats demonstrated a phenotype consistent with peripheral muscle dysfunction. They had reduced cardiolipin levels by 6.8% (P=0.007) and impaired cardiolipin maturation, as reflected by tafazzin expression. They also exhibited contractile dysfunction, titin hyperphosphorylation, fiber atrophy, and increased oxidative stress markers. Collectively, these findings support the idea that skeletal muscle in HFpEF is not merely deconditioned, but biologically altered at the mitochondrial and sarcomeric level.
Elamipretide treatment improved whole-muscle force in both studied muscle types. In the soleus, force increased by 8.2% (P=0.041), and in the extensor digitorum longus (EDL), force increased by 10.9% (P=0.016). These are modest but meaningful changes at the whole-muscle level, suggesting improved integrated muscle performance.
Single-fiber mechanics showed a more pronounced response in the soleus, with a 173.2% increase in contractile function (P<0.001). In the EDL, single-fiber contractile function improved by 66.0%, although this was not statistically significant. The difference between whole-muscle and fiber-level results may reflect variability, muscle-specific physiology, or sample-size constraints. Still, the direction of effect was consistently favorable.
Elamipretide also normalized titin phosphorylation, decreasing it by 35.4% in soleus and 40.2% in EDL, both with P<0.001. This is notable because titin phosphorylation can influence muscle stiffness and force transmission. By reducing hyperphosphorylation, elamipretide may have helped restore a more functional contractile state.
Muscle atrophy was also attenuated. Compared with untreated HFpEF rats, elamipretide prevented fiber loss and improved muscle size metrics, with increases of 49% in soleus (P=0.001) and 54.8% in EDL (P<0.001). Prevention of atrophy is clinically relevant because reduced muscle mass contributes to frailty, reduced mobility, and lower exercise tolerance in HFpEF.
At the mitochondrial level, the authors report improved function, presumably through cardiolipin-mediated enhancement of oxidative phosphorylation. While the abstract does not provide all respiratory parameters, the overall interpretation is that membrane stabilization translated into better bioenergetic efficiency, which then supported improved muscle mechanics and structural integrity.
Results interpreted in context
The findings provide a coherent biological chain: HFpEF was associated with cardiolipin abnormalities and oxidative stress in skeletal muscle; these changes were linked to impaired force generation and atrophy; and elamipretide partially reversed these abnormalities. The pattern is consistent with a mitochondria-centered mechanism rather than a purely hemodynamic explanation.
Importantly, the study examined both fast- and slow-twitch muscles. The soleus, a predominantly oxidative muscle, showed particularly robust improvement, which may align with the mechanism of mitochondrial stabilization. The EDL also benefited, suggesting that the effect is not restricted to one fiber type, although the magnitude and statistical certainty were less uniform.
Expert commentary
This study adds to a growing literature suggesting that HFpEF is a systemic syndrome involving skeletal muscle, mitochondria, inflammation, and metabolic dysregulation. It is mechanistically attractive because it targets cardiolipin, a structural determinant of mitochondrial efficiency, rather than focusing only on downstream symptoms.
Several limitations should temper interpretation. First, this is an animal study, and rodent HFpEF models do not fully reproduce the heterogeneity of human HFpEF. Second, the study used female rats, which is clinically relevant because HFpEF is common in women, but sex-specific effects still require broader validation. Third, the abstract provides limited detail on mitochondrial respiration data, effect sizes beyond percentages, and whether the improvements in muscle performance translated into better exercise capacity or systemic functional outcomes. Fourth, the absence of detailed safety data in the abstract means tolerability cannot be assessed here.
From a translational perspective, elamipretide has been studied previously in other mitochondrial disorders and cardiovascular settings, but clinical efficacy has been variable and not yet established as standard care. Therefore, these results should be viewed as hypothesis-generating rather than practice-changing. The most useful next steps would be studies in larger animal cohorts, mechanistic work linking cardiolipin restoration to whole-body exercise tolerance, and ultimately well-designed human trials with functional endpoints such as peak VO2, 6-minute walk distance, and patient-reported quality of life.
Conclusion
In this HFpEF rat model, elamipretide improved skeletal muscle force, reduced titin hyperphosphorylation, and prevented atrophy while apparently enhancing mitochondrial function. The study supports cardiolipin stabilization as a promising strategy for addressing skeletal muscle dysfunction in HFpEF. Although the findings are preclinical, they strengthen the rationale for targeting mitochondrial quality as part of future HFpEF therapeutics.
Funding and clinicaltrials.gov
The abstract does not report funding information or a clinicaltrials.gov registration number. As a preclinical animal study, it is not expected to have a clinical trial registry entry.
References
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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