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. 2025 Jun;16(3):e13843.
doi: 10.1002/jcsm.13843.

MyoMed205 Counteracts Titin Hyperphosphorylation and the Expression of Contraction-Regulating Proteins in a Rat Model of HFpEF

Beatrice Vahle  1 , Antje Schauer  1 , Antje Augstein  1 , Maria-Elisa Prieto Jarabo  1 , Janet Friedrich  1 , Peggy Barthel  1 , Anita Männel  1 , Norman Mangner  1 , Siegfried Labeit  2   3 , T Scott Bowen  4 , Axel Linke  1 , Volker Adams  1
Affiliations

MyoMed205 Counteracts Titin Hyperphosphorylation and the Expression of Contraction-Regulating Proteins in a Rat Model of HFpEF

Beatrice Vahle et al. J Cachexia Sarcopenia Muscle. 2025 Jun.

Abstract

Background: Heart failure with preserved ejection fraction (HFpEF) is associated with exercise intolerance, accompanied by alterations in the peripheral skeletal muscle (SKM). We have recently shown that titin, a giant sarcomere protein, is hyperphosphorylated in HFpEF. MuRF1 is a muscle-specific ubiquitin E3-ligase that interacts with titin. Blocking this interaction via small molecules (MyoMed205) can improve muscle function and mitochondrial activity in HFpEF. This study aimed to investigate the impact of MyoMed205 on titin phosphorylation and its association with changes in muscle structure and function.

Methods: Obese ZSF1 rats with established HFpEF received rat chow with (n = 15) or without (n = 15) MyoMed205 and were compared with lean littermates (n = 15), serving as controls. After 12 weeks, in vitro SKM force, atrophy and titin-as well as contractile protein expression-were evaluated (soleus and extensor digitorum longus [EDL]). Statistical analysis was performed via multiple unpaired t-test or one-way ANOVA.

Results: In HFpEF, titin hyperphosphorylation by 13% in the EDL (p = 0.09) and 14% (p = 0.03) in the soleus muscle was evident. This hyperphosphorylation was driven in part by an increase in S11878 phosphorylation (EDL: +68%, p = 0.004; Sol: +23.8%, p = 0.03), which was linked to myofiber atrophy (r = -0.68, p = 0.006) and a decline in maximal specific muscle force (r = -0.54, p = 0.008). In the EDL, significant changes in protein expression related to atrophy (MuRF1 [+24.9%, p = 0.02], GDF8 [+20.6%, p = 0.09]) and calcium handling (slow troponin C [-46%, p = 0.02], fast troponin I [+35.8%, p = 0.02]) were found in HFpEF. All of the above-mentioned effects in HFpEF were almost completely abolished by MyoMed205 treatment, and significantly elevated titin expression was visible (+19.7%, pcon = 0.04, pHFpEF = 0.01).

Conclusions: Titin hyperphosphorylation may negatively impact skeletal muscle integrity and function in HFpEF. MyoMed205 reduced titin hyperphosphorylation and was associated with preserved skeletal muscle function and mass. Further studies are necessary to confirm the direct role of titin hyperphosphorylation on muscle function and to evaluate the therapeutic potential of MyoMed205 in HFpEF.

Keywords: HFpEF; MuRF1; MyoMed205; ZSF1; atrophy; contractile proteins; sarcopenia; skeletal muscle function; titin.

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Conflict of interest statement

V. A. and S. L. report a patent for MyoMed‐205, ID#704946 and further derivatives for its application to chronic muscle stress states (patent accession No. WO2021023643A1). B. V., A. S., A. A., M. E. P. J., P. B.; A. M. and T. S. B. declare no conflicts of interest. N. M. reports personal fees from Edwards Lifesciences, Medtronic, Biotronik, Novartis, Sanofi Genzyme, AstraZeneca, Pfizer, Bayer, Abbott, Abiomed and Boston Scientific, outside the submitted work. A. L. reports grants from Novartis, personal fees from Medtronic, Abbott, Edwards Lifesciences, Boston Scientific, Astra Zeneca, Novartis, Pfizer, Abiomed, Bayer, Boehringer and other from Picardia, Transverse Medical, Claret Medical, outside the submitted work. The funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

FIGURE 1
FIGURE 1
SKM rearrangement occurs earlier in the EDL than in the Sol during HFpEF development. (A) CSA soleus, (B) CSA EDL, as well as (C) maximal specific force and (D) titin phosphorylation of soleus and EDL from ZSF1‐control (con) (represented as scattered line) and ZSF1‐HFpEF rats (HFpEF). Samples were obtained from 6‐, 10‐, 15‐, 20‐ and 32‐week‐old rats. The results are expressed as median ± Min–Max (n = 4–5 per group) **** p < 0.0001 (A, B) or as x‐fold change versus control (scattered line, set to 1.0) ± SEM (n = 4–12 per group) * p < 0.05 versus con (C, D).
FIGURE 2
FIGURE 2
MyoMed205 has antiatrophic effects. CSA of (A) soleus and (B) EDL from ZSF1‐control (con) and untreated ZSF1‐HFpEF rats (HFpEF) as well as treated ZSF1‐HFpEF rats (MyoMed205) at 32 weeks of age. The results are expressed as median ± Min–Max (n = 4–5 per group). **** p < 0.0001.
FIGURE 3
FIGURE 3
Titin hyperphosphorylation in the Sol can be normalized by treatment with MyoMed205. Titin expression, as well as phosphorylation, was quantified via VAGE analysis in skeletal muscle homogenates of Sol obtained from ZSF1‐control (con) (represented as a solid line) and untreated ZSF1‐HFpEF rats (HFpEF) as well as treated ZSF1‐HFpEF rats (MyoMed205) at 32 weeks of age. The results are expressed as x‐fold versus control (solid line, set to 1.0) ± SEM (n = 8–14 per group). Representative stains and VAGE blots are depicted below (c = con, HF = HFpEF, M = MyoMed205). # p < 0.05 versus con, $ p < 0.05 versus HFpEF.
FIGURE 4
FIGURE 4
Titin degradation gets reduced, whereas hyperphosphorylation can be normalized by treatment with MyoMed205 in the EDL. Protein expression, as well as phosphorylation of titin, was quantified via VAGE analysis in SKM homogenates of EDL obtained from ZSF1‐control (con) (represented as a solid line) and untreated ZSF1‐HFpEF rats (HFpEF) as well as treated ZSF1‐HFpEF rats (MyoMed205) at 32 weeks of age. The results are expressed as x‐fold versus control (solid line, set to 1.0) ± SEM (n = 10–14 per group). Representative stains and VAGE blots are depicted below (c = con, HF = HFpEF, M = MyoMed205). # p < 0.05 versus con, $ p < 0.05 versus HFpEF.
FIGURE 5
FIGURE 5
PEVK phosphorylation strongly correlates with functional parameters in the SKM. Correlation analyses between S11878 phosphorylation and total titin phosphorylation in the Sol (A) and the EDL (B). In addition, a correlation between S11878 phosphorylation and SKM CSA (C) and maximal (max.) specific force in the EDL (D) was evident.
FIGURE 6
FIGURE 6
Ubiquitination, but not of MHC, is susceptible to MyoMed205, whereas MLC phosphorylation is significantly decreased only in HFpEF animal. MHC expression as well as ubiquitination of MHC and a 85‐kDa protein (A) and MLC isoform expression and phosphorylation (B) were quantified by WB analysis in skeletal muscle homogenates of EDL, obtained from ZSF1‐control (con) (represented as solid line) and untreated ZSF1‐HFpEF rats (HFpEF) as well as treated ZSF1‐HFpEF rats (MyoMed205) at 32 weeks of age. The results are expressed as x‐fold versus control (solid line, set to 1.0) ± SEM (n = 6–11 per group). Representative stains and blots are depicted below (c = con, HF = HFpEF, M = MyoMed205). # p < 0.05 versus con, $ p < 0.05 versus HFpEF.
FIGURE 7
FIGURE 7
MyoMed205 modulates expression of proteins associated with Ca 2+‐dependent muscle contraction. TnC, TnI, TnT and α‐ and β‐Tm expression was quantified by WB analysis of skeletal muscle homogenates of EDL obtained from ZSF1‐control (con) (represented as solid line) and untreated ZSF1‐HFpEF rats (HFpEF) as well as treated ZSF1‐HFpEF rats (MyoMed205) at 32 weeks of age. The results are expressed as x‐fold versus control (solid line, set to 1.0) ± SEM (n = 10–14 per group). Representative blots are shown below (c = con, HF = HFpEF, M = MyoMed205). # p < 0.05 versus con, $ p < 0.05 versus HFpEF.
FIGURE 8
FIGURE 8
Normalized expression of atrophy markers after treatment with MyoMed205. MuRF1 and GDF8 expression was quantified via WB analysis of skeletal muscle homogenates of EDL obtained from ZSF1‐control (con) (represented as solid line) and untreated ZSF1‐HFpEF rats (HFpEF) as well as treated ZSF1‐HFpEF rats (MyoMed205) at 32 weeks of age. The results are expressed as x‐fold versus control (solid line, set to 1.0) ± SEM (n = 10–14 per group). Representative blots are shown below (c = con, HF = HFpEF, M = MyoMed205). # p < 0.05 versus con, $ p < 0.05 versus HFpEF.
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