Empagliflozin treatment in a rat model of HFpEF did not counteract atrophic muscle properties but restored titin levels (0.93 vs 0.72 in untreated HFpEF; p<0.05) and prevented hyperphosphorylation.
RCT (n=54)
randomized
Does empagliflozin improve skeletal muscle compliance and titin expression in a rat model of HFpEF?
In a rat model of HFpEF, short-term empagliflozin treatment improved skeletal muscle compliance by modulating sarcomeric proteins like titin, despite not reversing muscle atrophy.
Absolute Event Rate: 0.93% vs 0.72%
p-value: p=<0.05
Abstract Introduction Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for nearly 50% of all HF cases. Contrary to HF with reduced ejection fraction, therapeutical options are limited. Sodium glucose cotransporter-2 inhibitors (SGLT2i), that were originally developed for the use as anti-diabetic drugs have been shown to reduce hospitalization and mortality in patients with HFpEF. Several studies evaluated the effect of SGLT2i on myocardial function, but did not focus on skeletal muscle (SKM) function. Since exercise intolerance in HFpEF is characterized by SKM dysfunction, this aspect should not be neglected. An earlier study from our group showed beneficial effects of SGLT2i on soleus muscle function, characterized by increased force and improved mitochondrial respiration, in female ZSF-1 rats, which is an eligible HFpEF model. The aim of this study was to evaluate muscular changes in the tibialis anterior (TA), with a specific focus on titin, an important protein for muscle function and elasticity. Methods In this study, 18 ZSF-1 lean (con) and 36 ZSF-1 obese rats (HFpEF) were used. At 24-weeks of age obese rats were randomized into control (HFpEF, n=19) and treatment group (HFpEF+SGLT2i, n=17), receiving Empagliflozin (SGLT2i) (30 mg/kg/d, p. o. ). Rats were treated for 8 weeks and finally TA tissue was collected for molecular and histological analyses. Titin phosphorylation and expression, were visualized by specifically staining vertical agarose gels. Data were analyzed by One-way ANOVA. * p0. 05, ** p0. 01 vs. controls; p0. 05, p0. 01, p0. 001 vs. HFpEF. Results A reduced muscle mass (-6. 7%, p = 0. 001) and cross-sectional area (CSA) (-32%, p 0. 0001) in HFpEF vs. con could not be restored by SGLT2i treatment. Nevertheless, regarding muscle compliance and sarcomere structure, SGLT2i was able to restore titin levels (con: 1. 0±0. 06 vs. HFpEF: 0. 72±0. 07** vs. HFpEFSGLT2i: 0. 93±0. 05) and to prevent titin hyperphosphorylation (con: 1. 0±0. 04 vs. HFpEF: 1. 25±0. 1* vs. HFpEFSGLT2i: 0. 69±0. 1*, ). The same changes, regarding protein expression and phosphorylation, could be observed for titins degradation product T2. Consistent with these data, SMYD-2 expression, which is important for titin preservation, was significantly reduced in HFpEF rats, but not in SGLT2i treated rats (con: 1. 0±0. 06 vs. HFpEF: 0. 76±0. 05* vs. HFpEFSGLT2i: 0. 86±0. 05). In line with these data, SGLT2i prevented decreased Myosin Light Chain (MLC) -2 expression (con: 1. 0±0. 05 vs. HFpEF: 0. 78±0. 02** vs. HFpEFSGLT2i: 0. 83±0. 05*), as well as phosphorylation (con: 1. 0±0. 04 vs. HFpEF: 0. 83±0. 05* vs. HFpEFSGLT2i: 0. 87±0. 06), which is crucial for muscle contractility. Conclusions Regarding these data, we may conclude that short term SGLT2i-treatment, did not counteract atrophic muscle properties in HFpEF, but led to improved muscle compliance, by modulating expression and -phosphorylation of important sarcomeric proteins.
Vahle et al. (Mon,) conducted a rct in Heart failure with preserved ejection fraction (HFpEF) (n=54). Empagliflozin vs. Control (untreated HFpEF) was evaluated on Titin levels (p=<0.05). Empagliflozin treatment in a rat model of HFpEF did not counteract atrophic muscle properties but restored titin levels (0.93 vs 0.72 in untreated HFpEF; p<0.05) and prevented hyperphosphorylation.