Elamipretide (SS-31) improves skeletal muscle performance in HFpEF rats by stabilizing cardiolipin
Background
Exercise intolerance, a hallmark of Heart Failure with preserved Ejection Fraction (HFpEF), is significantly driven by skeletal muscle and mitochondrial dysfunction. Current therapies for HFpEF often fall short in addressing these peripheral manifestations, leaving a critical gap in improving patient quality of life. Prior research has linked mitochondrial dysfunction in HFpEF to altered cardiolipin integrity, a key phospholipid in the inner mitochondrial membrane essential for optimal oxidative phosphorylation. This suggests that stabilizing cardiolipin could be a viable therapeutic strategy, making Elamipretide, a known cardiolipin-stabilizing agent, a promising candidate to investigate.
Study Design
Researchers investigated Elamipretide's effects in female Zucker fatty spontaneously hypertensive heart failure F1 hybrid rats. The study included lean controls (n=10) and obese HFpEF rats (n=24). At 20 weeks of age, HFpEF rats were randomized to receive either NaCl (n=12) or Elamipretide (dose not specified in abstract) for 12 weeks. Skeletal muscle tissue was then collected to assess whole-muscle force, single-fiber mechanics, mitochondrial respiration, histology, and molecular analyses using techniques like qPCR for gene expression and ELISA for protein levels.
Results
HFpEF rats exhibited significant skeletal muscle pathology, including reduced cardiolipin levels by -6.8% (P=0.007), impaired cardiolipin maturation (indicated by tafazzin expression), contractile dysfunction, titin hyperphosphorylation, fiber atrophy, and increased oxidative stress markers. Elamipretide treatment remarkably ameliorated these deficits. Whole muscle contractile function improved significantly in both the soleus (+8.2%, P=0.041) and extensor digitorum longus (+10.9%, P=0.016) muscles. Single-fiber mechanics also saw substantial gains, with the soleus improving by +173.2% (P<0.001).
Elamipretide prevented muscle atrophy, increasing fiber size by +49% in the soleus (P=0.001) and +54.8% in the extensor digitorum longus (P<0.001). Furthermore,
titinphosphorylation was reduced (-35.4% in soleus, P<0.001; -40.2% in extensor digitorum longus, P<0.001), and mitochondrial function improved, likely via cardiolipin-mediated enhancements inoxidative phosphorylation.
Key Findings
- HFpEF rats showed reduced cardiolipin levels by -6.8% (P=0.007) and skeletal muscle dysfunction.
- Elamipretide improved whole muscle contractile function by +8.2% (soleus) and +10.9% (extensor digitorum longus).
- Single-fiber contractile function in the soleus muscle increased by +173.2% (P<0.001) with Elamipretide.
- Elamipretide prevented muscle atrophy, increasing fiber size by +49% (soleus) and +54.8% (extensor digitorum longus).
- Mitochondrial function improved, associated with cardiolipin stabilization and enhanced
oxidative phosphorylation.
Why It Matters
This study highlights Elamipretide's potential to directly address skeletal muscle weakness and exercise intolerance in HFpEF, a critical unmet need for patients. By targeting mitochondrial dysfunction and stabilizing cardiolipin, Elamipretide offers a mechanism distinct from current cardiac-centric HFpEF treatments. While this is a preclinical animal study, the significant improvements in muscle function and mitochondrial health suggest a promising therapeutic avenue. Future research will need to translate these findings into human clinical trials to establish optimal dosing and long-term efficacy, but it provides a strong rationale for exploring mitochondrial-targeted therapies in HFpEF.
elamipretide
ss-31
hfpef
mitochondrial-dysfunction
skeletal-muscle
cardiolipin