Molecular mechanisms underlying sarcopenia in heart failure

Abstract

The loss of skeletal muscle, also known as sarcopenia, is an aging-associated muscle disorder that is disproportionately present in heart failure (HF) patients. HF patients with sarcopenia have poor outcomes compared to the overall HF patient population. The prevalence of sarcopenia in HF is only expected to grow as the global population ages, and novel treatment strategies are needed to improve outcomes in this cohort. Multiple mechanistic pathways have emerged that may explain the increased prevalence of sarcopenia in the HF population, and a better understanding of these pathways may lead to the development of therapies to prevent muscle loss. This review article aims to explore the molecular mechanisms linking sarcopenia and HF, and to discuss treatment strategies aimed at addressing such molecular signals.

Keywords: Heart failure; inflammation; mitochondria; proteostasis; sarcopenia; skeletal muscle.

Figure 1.

Molecular mechanisms linking heart failure (HF) and sarcopenia. HF patients have reduced exercise tolerance, malnutrition, and altered hormonal signaling, including changes to aldosterone, angiotensin, cortisol, and catecholamine levels, all of which are linked to muscle wasting. Both HF and sarcopenia are associated with mitochondrial changes, including loss of maximal energy production and altered fuel utilization, increased oxidative stress, changes to mitochondrial fission/fusion leading to structural abnormalities, mitochondrial DNA (mtDNA) damage, and reduced mitochondrial protein quality control. Both HF and sarcopenia also have altered protein production and turnover, most notably involving autophagy and the ubiquitin-protease system (UPS), leading to proteostatic stress. Finally, HF is associated with chronic inflammation, particularly as evidenced by increased cytokine signaling involving TNF-α, IL-1, and IL-6, leading to muscle loss.

Figure 2.

Overview of activity-related, nutritional, and hormonal changes in heart failure (HF) leading to muscle loss. HF patients have exercise intolerance and reduced mobility, leading to reduced exercise capacity. Some HF patients have reduced appetite or digestive issues in the gastrointestinal (GI) tract, leading to malnutrition and reduced protein intake, limiting the ability to sustain muscle growth. HF is also associated with increased renin-angiotensin-aldosterone system (RAAS) signaling, which promotes muscle loss over time. Finally, hormonal changes seen in HF, including growth hormone, catecholamine, ghrelin, and testosterone signaling, all drive an imbalance in catabolism over anabolism, resulting in muscle loss.

Figure 3.

Changes to mitochondrial activity, behavior, and function common to failing myocardium and muscle tissue in sarcopenia. Mitochondria carry out a wide breadth of essential functions in the heart and muscle, and nearly all of these functions are dysregulated in heart failure and sarcopenia. Changes along the electron transport chain (Complexes I-IV and ATP synthase) lead to reduced ATP generation and increase superoxide release. Fuel utilization shifts from predominately fatty acids to alternative fuels, including glucose. Mitochondrial DNAs (mtDNAs) are damaged and released, leading to reduced mitochondrial biogenesis and activation of the innate immune response. Similarly, mitochondrial damage-associated molecular patterns (DAMPs) are exposed, triggering an immune response. Mitochondrial dynamics, including fission and fusion of established mitochondria, are altered, and reduced protein quality control can cause proteostatic stress in the cell.

Figure 4.

Overview of molecular regulators of proteostasis. Maintenance of the proteome, including synthesis of new proteins and degradation of old and damaged proteins, is dysregulated in both the failing heart and sarcopenic muscle. Signal transducers linking hormonal and nutritional changes to protein synthesis are conserved between the heart and peripheral muscle, including mitogen-activated protein kinase (MAPK), phosphatidylinositol-3-kinase (PI3K) / protein kinase B (AKT), AMP-activated protein kinase, and mammalian target of rapamycin (mTOR). Signals promoting proteolysis include Forkhead box O (FoxO) proteins, which can promote transcription of F-box protein 32 (FBXO32) to increase expression of Atrogin-1 to activate the ubiquitin protease system (UPS). Similarly, activation of nuclear factor κB (NF-κB) triggers transcription of TRIM63 to drive Muscle RING-finger protein-1 (MuRF-1) expression and promote UPS. Kruppel-like factors (KLFs) are promoted by inactivity to inhibit protein synthesis.

Figure 5.

Overview of cytokine changes in myocardium and skeletal muscle during Heart Failure (HF). HF can drive a wide breadth of inflammatory changes. Some of these include elevated pro-inflammatory hormonal signaling, gut edema allowing bacterial translocation, and exposure of damage-associate molecular patterns (DAMPs), leading to the release of cytokines including tumor necrosis factor (TNF) and interleukins (IL) 1 and 6. TNF can cause apoptosis, elevated reactive oxygen species (ROS), and mitochondrial DNA (mtDNA) damage in the musculature, leading to muscle damage and degradation. Transcription factors, including the Forkhead box O (FOXO) nuclear factor κB (NF-κB) families, are activated by cytokines, leading to altered proteostasis and activation of the ubiquitin-protease system (UPS).