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. Author manuscript; available in PMC: 2022 Mar 1.
Published in final edited form as: Curr Opin Cardiol. 2021 Mar 1;36(2):219–226. doi: 10.1097/HCO.0000000000000824

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

Eng Leng Saw 1, Swetha Ramachandran 2, Maria Valero-Muñoz 1, Flora Sam 1
PMCID: PMC7895420  NIHMSID: NIHMS1665345  PMID: 33394707

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 on HFpEF provide insights into the pathophysiological alterations in skeletal muscle structure and function and several molecular mechanisms have been identified. 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 function in HFpEF.

Keywords: HFpEF, exercise intolerance, dyspnea, fatigability, skeletal muscle dysfunction

1. Introduction

Heart failure (HF) is a global epidemic. Its prevalence is projected to increase by 46% from 2012 to 2030, resulting in greater than eight million Americans over 18 years of age with HF (1*). Of those with HF, about half have HF with preserved ejection fraction (HFpEF) while the other half have HF with reduced ejection fraction (HFrEF).

HFpEF is a clinical syndrome characterized by signs and symptoms of HF due to structural and functional abnormalities of the heart with normal left ventricular ejection fraction (≥50%). HFpEF is associated with progressive symptoms eventually leading to poor quality of life, substantial health-care costs and resource utilization, significant morbidity, and premature mortality (2*). Furthermore, its prevalence is growing at a disproportionate rate likely due to the increasing prevalence of risk factors such as aging, obesity, hypertension, diabetes, and atrial fibrillation (3, 4). The pathophysiology of HFpEF is heterogeneous, in part due to its association with multiple comorbidities, and this has hindered the process to understand this disease. As a result, unlike HFrEF, there are still no evidence-based treatments to improve morbidity and mortality in HFpEF. Thus, proceeding with a more precise approach is needed to study this complex disease (5, 6).

Despite phenotypic heterogeneity amongst HFpEF patients, a common feature is exercise intolerance. The etiology of this exercise intolerance in HFpEF is posited to be not only due to reduced cardiac reserve but also impaired pulmonary reserve as well as peripheral and respiratory skeletal muscle dysfunction (7, 8). In this review, we will discuss the clinical presentation, pathophysiology, and molecular mechanisms that are associated with skeletal muscle dysfunction in HFpEF patients and potential therapies to specifically target skeletal muscle.

2. Clinical presentation

Impaired peak oxygen uptake (VO2peak), which directly reflects maximal oxygen uptake (VO2max) is manifested as exercise intolerance. It can present clinically as dyspnea or easy fatigability in HFpEF patients (9*). Typically, this has been thought to be due to decreased oxygen delivery. Many studies focused on central cardiovascular abnormalities in HFpEF, such as chronotropic incompetence and impaired augmentation of stroke volume in the setting of decreased left ventricular compliance (10, 11). However, there is growing evidence to suggest that skeletal muscle dysfunction in the peripheral limbs is a major limitation of exercise capacity in HFpEF (12), with impairment in respiratory muscle also contributing to exercise intolerance (13, 14).

Dhakal et al. showed that diminished peripheral oxygen extraction was the leading cause of exercise intolerance in HFpEF patients and this was closely associated with decreased VO2peak (15). More recent studies also showed that peripheral skeletal muscle dysfunction may worsen peripheral oxygen extraction and thus also contribute to exercise intolerance and fatigability (16*, 17*). Furthermore, respiratory muscle dysfunction occurs in 30% of HFpEF patients and these patients also present with dyspnea in addition to exercise intolerance (13, 14). Prior studies showed that exercise training improved peripheral oxygen extraction and VO2peak in HFpEF patients (18, 19**). These clinical observations suggest that targeting peripheral oxygen extraction, at the skeletal muscle level to improve exercise capacity, may be more beneficial than interventions directed at central cardiac function in HFpEF.

Presently, there are no standardized ways to clinically measure skeletal muscle dysfunction although there are proposed screening tools and blood tests. A screening test for sarcopenia based on age, grip strength, and calf circumference, was shown to be a significant predictor of future HF events (20). Elevated levels of myostatin, a myokine, directly correlates with chronic HF and inversely correlates with muscle mass, but its significance in HFpEF is unknown (21*). Additionally, measurements of circulating malondialdehyde (MDA) and 4-hydroxy-2E-nonenal (4-HNE) from lipid peroxidation are potential biomarkers for sarcopenia in older adults (22, 23), but their utility as a measure of skeletal muscle dysfunction in HFpEF has not been demonstrated.

3. Skeletal muscle dysfunction

Various abnormalities are implicated in skeletal muscle dysfunction in HFpEF patients (24). At a macroscopic level, Haykowsky et al. reported that the percent of both total lean body and leg mass were significantly reduced in HFpEF patients compared to age-matched healthy controls, suggesting the presence of skeletal muscle atrophy (25). Importantly, such changes correlated well with reduced VO2peak in HFpEF patients (25). Additional studies investigating skeletal muscle composition found that HFpEF patients have increased thigh intermuscular fat despite a similar amount of subcutaneous fat compared to age-matched healthy controls. Notably thigh intermuscular fat to skeletal muscle ratio was inversely associated with VO2peak in these patients (26, 27).

At a microscopic level, biopsy of vastus lateralis muscles from HFpEF patients revealed a reduced percentage of oxidative type-1 fibers and an increased percentage of glycolytic type-2 fibers, (i.e., a reduced type-1-to-type-2 fiber ratio) compared to age-matched control subjects (28, 29). Type-1 fibers have greater oxidative capacity and mitochondrial density and contribute substantially to the ability to perform sustained aerobic exercise. Percentage of type-1 fibers is an independent predictor of VO2peak, thus a reduction in type-1 fibers reduces the skeletal muscle oxidative capacity and limits exercise capacity (28, 29). Additionally, the capillary to fiber ratio was reduced in HFpEF patients which could presumably lead to decreased muscle blood flow, oxygen transport and extraction in skeletal muscle (28). In the following section, we will further discuss the molecular mechanisms that may be associated with these pathophysiological alterations in skeletal muscle in HFpEF.

4. Molecular mechanisms associated with skeletal muscle dysfunction

Muscle atrophy

Muscle atrophy, as a result of cellular shrinkage, is caused by decreased protein synthesis as well as enhanced degradation of protein and cellular components. To date, several molecular signaling pathways have been associated with muscle atrophy, such as insulin growth factor-1 (IGF-1)/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt1) pathway, myostatin pathway, ubiquitin-proteasome pathway, and autophagy-lysosome pathway (reviewed in (30*)) (Figure 1). Akt1 controls both protein synthesis via mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase beta-1 (S6K1) and protein degradation via transcription factor forkhead box protein O (FoxO). Activation of the IGF-1/P3K/Akt1 pathway promotes protein synthesis and muscle hypertrophy while inactivation of this pathway allows FoxO to transcriptionally activate genes such as muscle-specific ubiquitin E3 ligases muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx/atrogin-1) that are involved in protein degradation (31*). Further, myostatin promotes muscle atrophy through mothers against decapentaplegic homology (SMAD)-2/3/2 and FoxO-dependent pathway (reviewed in (32*)). In terms of the ubiquitin-proteasome pathway, MuRF1 and MAFbx/atrogin-1 are upregulated to facilitate ubiquitination and hence protein degradation following muscle disuse (33*). Autophagy is triggered by the assembly of a regulatory complex (containing vacuolar protein sorting (VPS)-15, VPS-34, autophagy and beclin 1 regulator (ambra1), beclin1, barkor) and followed by the recruitment of microtubule-associated protein 1A/1B-light chain 3 (LC3) to the nascent autophagosome. The damaged organelles are sequestered by the autophagosome and shuttled to the lysosome for degradation (34*).

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

Figure 1.

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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.

Muscle atrophy has been described in several rodent models of HFpEF and associated with some of these pathways. In Dahl salt-sensitive HFpEF rats, IGF-1 gene expression and Murf-1 protein expression were significantly reduced in the soleus (i.e. predominant oxidative type-1 fiber (35, 36)) compared to control rats. However, calpain activity and proteasome activity in soleus were comparable between control and HFpEF rats (37). Conversely, in the diaphragm (i.e. predominant glycolytic type-2 fiber (38)) of HFpEF rats, IGF-1 gene expression and proteasome activity were comparable, Murf-1 protein expression was increased, and calpain activity was decreased compared to control rats (37). Additionally, the same study demonstrated that there was no change in the expression of autophagy marker (i.e. LC3-II/I ratio) in either soleus or diaphragm, suggesting autophagy was not involved in the pathophysiology of muscle atrophy in HFpEF (37). However, Bowen et al. reported that LC3-II/I ratio was significantly decreased in the extensor digitorum longus (EDL) muscle (i.e. predominant glycolytic type-2 fiber (39)), but not the soleus muscle, of the obese/hypertensive HFpEF rats (40). Altogether, these results suggest that muscle atrophy is differentially regulated in limb skeletal muscle and respiratory muscle in HFpEF. However, more evidence is required to support these results as these were only derived from two independent studies. Interestingly, Hirata et al. also showed that hyperglycemia also induced muscle atrophy in the skeletal muscles by suppressing the expression of WW domain-containing E3 ligase (WWP1), and consequently increased the expression of transcription factor krüppel-like factor 15 (KLF15) and its downstream targeted atrophy-related genes (41*). Since type-2 diabetes is a common comorbidity seen in HFpEF, future studies may consider examining the involvement of these factors.

Reduced oxidative capacity

Peroxisome proliferator-activator receptors (PPARs) such as PPARα, PPARβ (also known as PPARδ) and PPARγ belong to the nuclear receptor superfamily of transcription factors (42). PPARβ/δ is ubiquitously expressed in skeletal muscle (42). It dimerizes with retinoid X receptor (RXR) and transcriptionally activate target genes such as PPAR-γ coactivator-1α (PGC-1α) (43). PGC-1α is a transcriptional co-activator. In conjunction with nuclear respiratory factor-1/−2 (NRF-1/2), it promotes the transcription of genes that are involved in mitochondrial biogenesis. Additionally, with myocyte enhancer factor-2 (MEF-2), it activates the transcription of genes involved in muscle fiber type switching (44–46). Further, PPARβ/δ/RXRx/PGC-1α complex also activates genes related to free-fatty acid (FFA) metabolism and energetics (46, 47) (Figure 2).

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

Figure 2.

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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.

In HFpEF, reduced skeletal muscle oxidative capacity diminishes the production of ATP that is required to sustain muscle contraction (28, 29), exacerbating exercise intolerance (48). Considering that PPARβ/δ and PGC-1α are the key regulators of oxidative capacity in skeletal muscle (44–47, 49), alteration of these signaling molecules could contribute to oxidative dysfunction in HFpEF. Interestingly, current evidence from HFpEF animal models has not supported the observations seen in HFpEF patients (28, 29). Soleus and diaphragm from hypertensive HFpEF rats showed comparable expression of PGC-1α, mitochondrial function and oxidative stress as control rats (37). In contrast, another study showed an increase in PGC-1α protein expression accompanied by an increase of oxidative type-1 fibers, a decrease in glycolytic type-2 fibers, and fiber hypertrophy of type-1 fibers despite mitochondrial and contractile dysfunction in the diaphragm of obese/hypertensive HFpEF rats compared to control rats (50). The observed differences are likely due to the animal models not recapitulating the skeletal muscle dysfunction observed in HFpEF patients, or the functional differences between different types of muscles (respiratory muscles versus limb muscles). Thus, further investigation is certainly needed to thoroughly characterize skeletal muscle function in preclinical models of HFpEF.

Altered skeletal muscle metabolism and energetics

Altered metabolism also plays a role in skeletal muscle dysfunction in HFpEF. Severe exercise intolerance has been linked to early depletion as well as a delay in the recovery of phosphocreatine (PCr, a high-energy phosphate) in the skeletal muscle of the HFpEF patients compared to HFrEF and non-HF patients during and after exercise (48). These results suggest that ATP synthesis is impaired/diminished in HFpEF, which could be due to metabolic changes and/or reduced oxidative capacity in skeletal muscle. As glycolytic type-2 fibers increase in HFpEF patients (28, 29), it is logical to postulate that skeletal muscle metabolism is dependent on glucose for ATP synthesis in these patients. However, a previous study showed that AMP-activated protein kinase (AMPK)/glucose transporter (GLUT)-4 signaling is suppressed in skeletal muscle in obese/hypertensive HFpEF rats and patients with metabolic syndrome (but not HFpEF), but might suggest that skeletal muscle glucose metabolism is diminished in HFpEF (51). Of note, it has also been described that increased circulating lipid metabolites, particularly the long-chain acylcarnitine metabolites derived from β-oxidation of FFA, in HFpEF patients may indicate that FFA metabolism is predominant in HFpEF (52). Thus, in-depth investigations are needed to address the skeletal muscle metabolic profile and how comorbidities could further alter the metabolism and energetics and ultimately exacerbate exercise intolerance in HFpEF.

Impaired skeletal muscle microvasculature

Previous studies have showed that capillary rarefaction (28), but not macro-vessels (53), is associated with reduced limb blood flow in HFpEF patients during exercise (54, 55). To our knowledge, there is no data on skeletal muscle capillary rarefaction in animal models of HFpEF. Capillary rarefaction disrupts the microvascular oxygenation dynamics in skeletal muscle (56*), and one of the mechanisms that could possibly contribute to such rarefaction is impaired nitric oxide (NO)-mediated vasodilation (57*). Nitric oxide is needed to enhance the expression of proangiogenic factor vascular endothelial growth factor (VEGF) through hypoxia-inducible factor (HIF)-1α-dependent signaling to promote angiogenesis in endothelial cells during muscle regeneration (58*) (Figure 3). Furthermore, PGC-1α also enhances VEGF expression through estrogen-related receptor-α (ERR-α) in skeletal myocytes during exercise (59–61*). These results indicate that NO and PGC-1α are important upstream regulators that modulate VEGF expression in skeletal muscle (Figure 3). However, it is unknown if VEGF expression is altered by upstream regulators or if there is defective NO-/PGC-1α-mediated signaling in HFpEF. Nonetheless, aging studies in skeletal muscles showed that muscle-derived VEGF expression was significantly reduced and correlated to capillary rarefaction in aged men and women before and after exercise (62, 63). Since HFpEF is the most common form of HF in older adults and is associated with advanced age, further insights into how VEGF and its associated signaling is involved in skeletal muscle capillary rarefaction in HFpEF will be informative.

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

Figure 3.

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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.

5. Targeting the skeletal muscle as a therapeutic intervention

To date, exercise training, in addition to caloric restriction, is one of the interventions shown to improve outcomes in HFpEF patients (reviewed in (64*)). A previous study showed that peak arterial-venous oxygen difference (i.e. an indication of peripheral oxygen extraction) and VO2peak are significantly higher in elderly stable compensated HFpEF patients after four months of endurance exercise training, suggesting that the beneficial effect of exercise training may be mediated through peripheral tissues such as skeletal muscle (18). A recent randomized clinical trial demonstrated that both high-intensity interval training (HIIT) and moderate continuous training (MCT) are effective in improving cardiac function, VO2peak, and quality of life in HFpEF patients, with HIIT resulting in better outcomes (19**). Additionally, a single-blinded study showed that endurance exercise training improved VO2peak but without altering endothelial function in the right brachial artery or arterial stiffness of the left common carotid artery in elderly HFpEF patients (65). In contrast, preclinical studies showed that neither MCT nor HIIT reversed the alterations in the diaphragm (50) or skeletal muscle (40), but both exercise regimens preserved endothelial cell dysfunction in the aorta (66), in the obese/hypertensive HFpEF rats. These discordant findings between animal and human HFpEF demonstrate the complex pathophysiology of HFpEF and suggest that skeletal muscle dysfunction may not be fully recapitulated in the obese/hypertensive HFpEF rats. Thus, additional studies are warranted.

In addition to exercise training, targeting the endothelial-skeletal myocyte paracrine signaling via NO donors to restore NO balance is another intervention strategy (reviewed in (67*)). The INDIE-HFpEF randomized clinical trial (NCT02742129) showed that inhaled inorganic nitrite (i.e. NO donor) did not improve VO2peak and exercise capacity in HFpEF patients, but inadequate drug delivery from nebulizer was raised as an issue (68). A recently completed randomized trial investigated the effect of an oral formulation of inorganic nitrate supplementation in regulating the vasomotor dynamics in skeletal muscle in elderly HFpEF patients (NCT02918552), but the results have not been released. An ongoing phase II study of metformin is investigating the effect of targeting glucose metabolism and modulating secreted factor fibroblast growth factor 21 (FGF21) expression in skeletal muscle of HFpEF patients with pulmonary hypertension (RO1AG058659). Additional pharmacological agents are currently being investigated in skeletal muscle and are summarized in a recent literature review (67*).

6. Conclusion

There is presently no effective treatment for HFpEF likely due to an incomplete understanding of this heterogeneous syndrome. Therapy has been relegated to symptom control with diuretics. Exercise intolerance is the cardinal symptom of HFpEF and skeletal muscle dysfunction is a likely contributor. Additional studies are needed to carefully phenotype skeletal muscle dysfunction in both humans and appropriate preclinical models of HFpEF. This will increase the understanding of the pathophysiology of skeletal muscle dysfunction and allow for novel targeted therapy for HFpEF.

Key points:

  • Skeletal muscle dysfunction is associated with exercise intolerance in HFpEF

  • Pathological alterations in skeletal muscles include muscle atrophy, decreased oxidative capacity, altered metabolism and energetics, and microvascular rarefaction.

  • Exercise training is an effective intervention for HFpEF, but its effect on skeletal muscle function is poorly understood.

Acknowledgments

Funding Disclosure: National Institutes of Health RO1HL145985 to F.S.

Footnotes

Conflicts of interest: None

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