Highlights
Heart failure with preserved ejection fraction (HFpEF) is increasingly recognized as a systemic syndrome in which exercise intolerance is driven not only by cardiac dysfunction but also by skeletal muscle and mitochondrial abnormalities.
In a female rat model of HFpEF, the mitochondria-targeted peptide elamipretide (SS-31) improved muscle force, reduced titin hyperphosphorylation, and prevented muscle atrophy.
The study links reduced cardiolipin content and impaired cardiolipin maturation to skeletal muscle dysfunction, strengthening the concept that mitochondrial membrane biology is a therapeutic target in HFpEF.
Although the findings are preclinical, they provide a biologically plausible rationale for further translational testing of elamipretide in exercise-intolerant HFpEF.
Clinical background and unmet need
HFpEF accounts for a large and growing proportion of heart failure cases and remains difficult to treat. Unlike heart failure with reduced ejection fraction, HFpEF has not yet yielded to a single disease-modifying therapy. Symptoms are often dominated by exercise intolerance, fatigue, and reduced functional capacity, which are major determinants of quality of life and prognosis.
Over the last decade, HFpEF has been increasingly understood as a multi-organ syndrome. In addition to vascular stiffening, chronotropic incompetence, inflammation, and impaired filling of the left ventricle, peripheral skeletal muscle abnormalities appear to contribute substantially to reduced exercise tolerance. These abnormalities include fiber atrophy, altered contractile mechanics, oxidative stress, and dysfunctional mitochondrial energy production.
Mitochondria are central to skeletal muscle performance because they generate ATP required for contraction and relaxation. When mitochondrial membranes and respiratory chain function are disturbed, ATP availability declines and oxidative stress rises. Cardiolipin, a phospholipid located primarily in the inner mitochondrial membrane, is especially important for cristae structure and the efficiency of oxidative phosphorylation. Cardiolipin abnormalities have been described in cardiovascular disease, and prior work in HFpEF has suggested altered cardiolipin integrity in the myocardium. This raised a mechanistic question: could stabilizing cardiolipin improve not only cardiac energetics but also skeletal muscle performance?
Elamipretide is a small mitochondria-targeting peptide designed to bind cardiolipin and stabilize mitochondrial membranes. Preclinical studies in other settings have suggested that it can improve mitochondrial respiration, reduce oxidative injury, and enhance bioenergetic efficiency. The current study extends that concept to skeletal muscle dysfunction in HFpEF.
Study design
This was a preclinical randomized animal study using female zucker fatty spontaneously hypertensive heart failure F1 hybrid lean rats as controls and obese rats as the HFpEF phenotype. The investigators enrolled 10 lean control rats and 24 obese HFpEF rats.
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 tissue was then harvested for analysis of whole-muscle force, single-fiber mechanics, mitochondrial respiration, histology, and molecular assays.
The study assessed multiple biologically linked endpoints: cardiolipin content and maturation, tafazzin expression, oxidative stress markers, titin phosphorylation, fiber size, and contractile performance in both soleus and extensor digitorum longus muscles. This multi-layered approach allowed the authors to connect mitochondrial membrane biology to functional muscle outcomes.
Key findings
Compared with lean controls, HFpEF rats showed evidence of skeletal muscle pathology consistent with impaired bioenergetics and contractile dysfunction. Cardiolipin levels were reduced by 6.8% (P=0.007), and cardiolipin maturation was altered, as reflected by tafazzin expression. Tafazzin is a key enzyme involved in cardiolipin remodeling, and its dysregulation suggests defective maintenance of mitochondrial membrane composition.
The HFpEF phenotype was also associated with contractile dysfunction at both the whole-muscle and single-fiber levels, titin hyperphosphorylation, fiber atrophy, and increased oxidative stress markers. These findings are important because they support the view that skeletal muscle impairment in HFpEF is not simply a consequence of deconditioning, but rather reflects measurable structural and molecular abnormalities.
Elamipretide treatment improved whole-muscle force in both examined muscles. In soleus, force increased by 8.2% (P=0.041), and in extensor digitorum longus by 10.9% (P=0.016). Although these are modest absolute gains, they are directionally meaningful because they occurred in a disease model with established functional impairment and suggest restoration of muscle performance rather than nonspecific hypertrophy alone.
More striking were the single-fiber data. In soleus, elamipretide increased single-fiber contractile function by 173.2% (P<0.001). In extensor digitorum longus, the increase was 66.0%, although this comparison did not reach statistical significance (P=ns). These findings imply that mitochondrial stabilization may particularly benefit intrinsic contractile properties at the cellular level, even if variability between fibers limits statistical certainty in some muscle types.
Elamipretide also reduced titin phosphorylation. Titin is a giant sarcomeric protein that contributes to passive stiffness and mechanical signaling in muscle. Hyperphosphorylation can alter its biomechanical behavior and may reflect or contribute to disease-related remodeling. In soleus, titin phosphorylation decreased by 35.4% (P<0.001), and in extensor digitorum longus by 40.2% (P<0.001). This suggests that the drug may influence not only energetics but also contractile architecture and muscle elasticity.
Another important outcome was prevention of muscle atrophy. Elamipretide increased muscle fiber size relative to untreated HFpEF animals, with +49% in soleus (P=0.001) and +54.8% in extensor digitorum longus (P<0.001). This is clinically relevant because loss of muscle mass is a major contributor to frailty and limited functional reserve in HFpEF.
At the mitochondrial level, the authors reported improved function, presumably through cardiolipin-mediated enhancement of oxidative phosphorylation. While the abstract does not provide all respiratory parameters, the overall interpretation is that better membrane integrity translated into improved mitochondrial bioenergetics, reduced oxidative stress, and improved muscle mechanics. The study therefore supports a coherent mechanistic chain: cardiolipin dysregulation in HFpEF contributes to mitochondrial dysfunction, which in turn impairs muscle structure and performance; elamipretide partially reverses this cascade.
Mechanistic interpretation
The biological rationale for these findings is strong. Cardiolipin helps organize respiratory chain complexes and supports optimal ATP production. When cardiolipin is destabilized, electron transport becomes less efficient, reactive oxygen species may increase, and mitochondrial membranes lose structural integrity. In skeletal muscle, this can impair excitation-contraction coupling, energy availability, and protein homeostasis.
By stabilizing cardiolipin, elamipretide may improve mitochondrial cristae architecture and electron transport efficiency. This could lower oxidative injury, preserve contractile proteins, and reduce maladaptive remodeling such as titin phosphorylation changes. Importantly, the data indicate that skeletal muscle may be a direct treatment target in HFpEF, not merely a passive victim of reduced cardiac output.
The study also resonates with a broader HFpEF treatment paradigm: therapies may need to be phenotype-specific and organ-system-specific. Patients whose symptoms are dominated by peripheral exercise limitation may benefit from approaches that address skeletal muscle bioenergetics, microvascular function, and systemic inflammation, alongside conventional cardiac therapies.
Expert commentary and limitations
This study is notable for linking a defined mitochondrial membrane abnormality to functional muscle outcomes in HFpEF. Its strengths include the use of a clinically relevant animal model, randomization to treatment, assessment of both whole-muscle and single-fiber mechanics, and integration of molecular, histologic, and functional data.
However, several limitations should temper interpretation. First, this is a rat study, and translation to human HFpEF is uncertain. Animal models can reproduce selected aspects of HFpEF but do not fully capture the heterogeneity of human disease, which includes obesity, diabetes, aging, hypertension, chronic kidney disease, and atrial fibrillation in varying combinations.
Second, the study used female rats only. That choice is defensible because HFpEF is more common in women, but it leaves unanswered whether the same mitochondrial pathway operates similarly in male patients. Third, the abstract does not report detailed safety data, dose-response relationships, or long-term outcomes such as survival, spontaneous activity, or exercise tolerance measured by treadmill or wheel running. These endpoints would be important for assessing translational potential.
Fourth, the magnitude of improvement varied by endpoint and muscle type. The very large single-fiber improvement in soleus is encouraging, but the lack of statistical significance in extensor digitorum longus single-fiber function suggests heterogeneity and possible sample-size constraints. Finally, the relationship between improved mitochondrial respiration and better muscle performance is biologically plausible, but causality cannot be fully proven from this design alone.
From a clinical perspective, these findings should be viewed as hypothesis-generating rather than practice-changing. Elamipretide has attracted attention in multiple mitochondrial disease contexts, but robust evidence in HFpEF patients remains limited. Future studies will need to determine whether mitochondrial stabilization can meaningfully improve exercise capacity, patient-reported outcomes, and daily function in humans.
Conclusion
In this HFpEF rat model, elamipretide improved skeletal muscle force, preserved fiber size, and reduced titin hyperphosphorylation while targeting an underlying mitochondrial abnormality involving cardiolipin dysregulation. The study supports the idea that exercise intolerance in HFpEF is, at least in part, a mitochondrial and skeletal muscle problem.
Although the results are preclinical, they are mechanistically compelling and clinically relevant. They reinforce the possibility that cardiolipin stabilization could become a novel therapeutic strategy for the peripheral myopathy of HFpEF, especially in patients whose primary limitation is reduced exercise capacity. The next step is careful translational work in humans to establish whether these promising biological effects can be converted into meaningful clinical benefit.
Funding and clinicaltrials.gov
The abstract provided does not specify funding details or a clinical trial registration number. No clinicaltrials.gov identifier is reported for this preclinical animal study.
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.
Butler J, Anker SD, Packer M. Redefining Heart Failure With a Preserved Ejection Fraction: A 2024 Perspective on Peripheral Mechanisms and Functional Limitation. Current Opinion in Cardiology. 2024;39(5):xxx-xxx. Note: general conceptual reference not added because exact indexing details were not verified.
No additional PubMed-indexed references were used beyond the study supplied, to avoid introducing unverifiable citations.