AUTHOR=Saw Eng Leng , Werner Louis Dominic , Zamani Payman , Chirinos Julio A. , Valero-Muñoz María , Sam Flora 

TITLE=Skeletal muscle phenotypic switching in heart failure with preserved ejection fraction

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2022.1016452

DOI=10.3389/fcvm.2022.1016452

ISSN=2297-055X

ABSTRACT=<sec><title>Background</title><p>Skeletal muscle (SkM) phenotypic switching is associated with exercise intolerance in heart failure with preserved ejection fraction (HFpEF). Patients with HFpEF have decreased type-1 oxidative fibers and mitochondrial dysfunction, indicative of impaired oxidative capacity. The <italic>SAUNA</italic> (<underline>SA</underline>lty drinking water/<underline>U</underline>nilateral <underline>N</underline>ephrectomy/<underline>A</underline>ldosterone) mice are commonly used in HFpEF pre-clinical studies and demonstrate cardiac, lung, kidney, and white adipose tissue impairments. However, the SkM (specifically the oxidative-predominant, <italic>soleus</italic> muscle) has not been described in this preclinical HFpEF model. We sought to characterize the <italic>soleus</italic> skeletal muscle in the HFpEF <italic>SAUNA</italic> mice and investigate its translational potential.</p></sec><sec><title>Methods</title><p>HFpEF was induced in mice by uninephrectomy, <italic>d</italic>-aldosterone or saline (Sham) infusion by osmotic pump implantation, and 1% NaCl drinking water was given for 4 weeks. Mice were euthanized, and the oxidative-predominant <italic>soleus</italic> muscle was collected. We examined fiber composition, fiber cross-sectional area, capillary density, and fibrosis. Molecular analyses were also performed. To investigate the clinical relevance of this model, the oxidative-predominant, <italic>vastus lateralis</italic> muscle from patients with HFpEF was biopsied and examined for molecular changes in mitochondrial oxidative phosphorylation, vasculature, fibrosis, and inflammation.</p></sec><sec><title>Results</title><p>Histological analyses demonstrated a reduction in the abundance of oxidative fibers, type-2A fiber atrophy, decreased capillary density, and increased fibrotic area in the <italic>soleus</italic> muscle of HFpEF mice compared to Sham. Expression of targets of interest such as a reduction in mitochondrial oxidative-phosphorylation genes, increased VEGF-α and an elevated inflammatory response was also seen. The histological and molecular changes in HFpEF mice are consistent and comparable with changes seen in the oxidative-predominant SkM of patients with HFpEF.</p></sec><sec><title>Conclusion</title><p>The HFpEF <italic>SAUNA</italic> model recapitulates the SkM phenotypic switching seen in HFpEF patients. This model is suitable and relevant to study SkM phenotypic switching in HFpEF.</p></sec>