Effects of Endurance Training on Detrimental Structural, Cellular, and Functional Alterations in Skeletal Muscles of Heart Failure With Preserved Ejection Fraction

Background: Heart failure with preserved ejection fraction (HFpEF) is underpinned by detrimental skeletal muscle alterations that contribute to disease severity, yet underlying mechanisms and therapeutic treatments remain poorly established. This study used a nonhuman animal model of HFpEF to better understand whether skeletal muscle abnormalities were (1) fiber-type specific and (2) reversible by various exercise training regimes. Methods and Results: Lean control rats were compared with obese ZSF1 rats at 20 weeks and then 8 weeks after sedentary, high-intensity interval training, or moderate continuous treadmill exercise. Oxidative soleus and glycolytic extensor digitorum longus (EDL) muscles were assessed for fiber size, capillarity, glycolytic metabolism, autophagy, and contractile function. HFpEF reduced fiber size and capillarity by 20%-50% (P < .05) in both soleus and EDL, but these effects were not reversed by endurance training. In contrast, both endurance training regimes in HFpEF attenuated the elevated lactate dehydrogenase activity observed in the soleus. Autophagy was down-regulated in EDL and up-regulated in soleus (P < .05), with no influence of endurance training. HFpEF impaired contractile forces of both muscles by 20% (P < .05), and these were not reversed by training. Conclusions: Obesity-related HFpEF was associated with detrimental structural, cellular, and functional alterations to both slow-oxidative and fast-glycolytic skeletal muscles that could not be reversed by endurance training.