Skeletal muscle (dys)function in heart failure with preserved ejection fraction

Abstract

Purpose of review: Skeletal muscle dysfunction contributes to exercise intolerance, which manifests as dyspnea and fatiguability in patients with heart failure with preserved ejection fraction (HFpEF). This review aims to summarize the current understanding of skeletal muscle dysfunction in HFpEF.

Recent findings: Animal and human studies in HFpEF provide insights into the pathophysiological alterations in skeletal muscle structure and function with the identification of several molecular mechanisms. Exercise training and novel pharmacological therapies that target skeletal muscle are proposed as therapeutic interventions to treat HFpEF.

Summary: There is evidence that skeletal muscle dysfunction plays a pathophysiological role in HFpEF. However, precise mechanistic insights are needed to understand the contribution of skeletal muscle dysfunction in HFpEF.

Figure 1.. Molecular pathways control protein synthesis and degradation in skeletal myocytes.

IGF-1 promotes protein synthesis through the PI3K/Akt1/mTOR pathway. Activation of Akt1 phosphorylates transcription factor FoxO and thus promotes its export from the nucleus to the cytoplasm. However, in the absence of IGF-1, FoxO is translocated to the nucleus and promotes the transcription of genes that are involved in protein degradation. Similarly, myostatin promotes FoxO- and Smad-2/3/2 dependent pathways and leads to protein degradation. Both MuRF1 and MAFbx1 are ubiquitin E3 ligases that facilitate the transfer of ubiquitin to protein. The polyubiquitinated protein is shuttled to the proteasome for degradation. In the autophagy-lysosome pathway, the assembly of the VPS15/VPS34/ambra1/beclin1/barkor complex triggers the formation of autophagosomes, where the damaged organelles are isolated and to which LC3 is recruited. The autophagosomes then fuses with lysosomes for degradation.

Figure 2.. The role of PPARβ/δ and PGC-1α in skeletal muscle.

PPARβ/δ dimerizes with the RXR complex and hence enhances PGC-1α expression. PGC-1α co-activates with NRF-1/2, MEF-2, and PPARβ/δ/RXR to promote transcription of genes that are involved in mitochondrial biogenesis, switching to oxidative type-1 fiber and FFA metabolism, respectively.

Figure 3.. PGC-1α and nitric oxide (NO)-induced angiogenesis in skeletal muscle.

In response to β-adrenergic stimulation and exercise, skeletal myocytes produce and secrete VEGF to promote angiogenesis by binding to VEGF receptors expressed on endothelial cells in a paracrine manner. In response to an ischemic milieu (such as during exercise), NO levels are increased and in return stimulates HIF-1α expression in endothelial cells. HIF-1α dimerizes with HIF-1β to form the transcription factor HIF-1 which in turn induces the production of VEGF. VEGF is then secreted and binds to the VEGF receptor expressed on the endothelial cells to promote angiogenesis to facilitate muscle regeneration.