Skeletal muscle accounts for 40%–50% of the total body weight and is an important component of the human body [15]. Under physiological conditions, muscle mass declines by an average of 0.47% and 0.37% per year in men and women, respectively. Such a decline can reach 1%–2% per year with aging [16]. In this regard, I. H. Rosenberg coined the term sarcopenia to describe skeletal muscle loss [17]. Sarcopenia refers to a form of muscle atrophy that occurs with aging and is characterized by a degenerative loss of skeletal muscle weight, mass and strength independent of weight gain or loss [18, 19]. Overall, 5%–13% of people aged more than 60 years have sarcopenia, whereas the prevalence in those above 80 years old exceeds 50% [19].

Sarcopenia is defined as low appendicular skeletal muscle mass (ASM), which means that the sum of the muscle mass of the extremities divided by the square of the height is less than two standard deviations from the reference value for young people of the same sex. Asian Working Group for Sarcopenia (AWGS) 2019 consensus defined sarcopenia as age-related loss of skeletal muscle mass plus loss of muscle strength and/or reduced physical performance [20]. In most cases, ASM is measured via dual-energy X-ray absorptiometry (DEXA); however, in some cases, bioelectrical resistance can be employed as an alternative. A cutoff value of 7.0 kg/m${}^2$ for men and 5.4 kg/m${}^2$ for women for muscle mass measurement via DEXA and a cutoff value of 7.0 kg/m${}^2$ for men and 5.7 kg/m${}^2$ for women for bioelectrical impedance measurement were suggested by the AWGS. In addition, grip strength (26 kg for men and 18 kg for women) and general gait speed (1.0 m/s) should be taken into account [20]. Given that these diagnostic methods are cumbersome and expensive, in recent years researchers have been working to explore biomarkers for the diagnosis and prediction of sarcopenia, such as serum creatinine, type VI collagen turnover-related peptides, and myokines [21].

Sarcopenia is independently associated with several cardiovascular diseases and their associated risk factors, including myocardial infarction, congestive HF, atrial fibrillation, and atherosclerosis [22, 23]. Sarcopenia may accelerate the progression of chronic diseases such as cancer and HF. Indeed, sarcopenia can be found in 20–50% of patients with heart failure with reduced ejection fraction (HFrEF) and is commonly associated with increased morbidity and mortality [2]. The prevalence of sarcopenia in patients with heart failure with preserved ejection fraction (HFpEF) was found to be 19.7% in the SICA-HF study (European multicenter study) [24, 25]. In turn, chronic HF can worsen the adverse outcomes associated with sarcopenia, including osteoporosis, falls, cachexia, frailty, rehospitalization, and death, which may be associated with HF-related malnutrition, altered hormone levels, inflammation, oxidative stress, autophagy, and apoptosis [26]. Bekfani et al. [27] have showed recently in skeletal muscle biopsies elevated levels of atrophy genes and proteins in patients with HFpEF compared to HFrEF and healthy controls. Furthermore, patients with HF showed distorted fatty acid oxidation, glucose oxidation and mitochondrial number and function. Patients with reduced muscle function showed elevated levels of inflammatory parameter and reduced fatty acid oxidation.

Very recently, an association between sarcopenia and depression has gradually attracted attention. Depression leads to alterations in neurological, immune, and endocrine functions, which are significantly associated with physical fitness. A meta-analysis including 10 studies revealed that sarcopenia remained significantly positively associated with depression after adjustment for potential confounders, such as age, gender, cognitive performance, and physical activity [28]. In China, a cohort study demonstrated that sarcopenia was also significantly associated with depressive symptoms after adjustment for confounders and that new-onset depressive symptoms were associated with muscle mass, suggesting that sarcopenia is an independent risk factor for depressive symptoms [29].

Unlike sarcopenia, cachexia is defined as complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. Its major clinical feature is a $>$5% oedema-free body weight loss during the previous 12 months or less. Cachexia is a generalized wasting process that may occur in 5–15% of patients with HF [2]. In sarcopenia, energy expenditure is not usually increased or it is even decreased, whereas in cachexia, it can be increased due to the hypermetabolic state, and the systemic inflammatory response is more severe in patients with cachexia [14, 30]. Sarcopenia in patients with chronic HF may eventually progress to cardiac cachexia. Previous clinical studies found that cachexia remained an independent predictor of death in patients with HF after adjustment for age, New York Heart Association (NYHA) classification, left ventricular ejection fraction (LVEF), and peak oxygen consumption [31]. Several studies have demonstrated that skeletal muscle is the first tissue to be lost and that the loss of adipose tissue gradually begins later during the course of HF. Thus, patients with HF may experience muscle loss before the onset of cachexia, and muscle loss can lead to increased cachexia [14].

A study conducted by Chen et al. [33] on the relationship between sarcopenia, depression, and cognitive function demonstrated that subjects with sarcopenia were significantly more malnourished than those without, and there was also a significant difference in nutritional scores between subjects with depressive symptoms. The most direct cause of malnutrition in patients with HF and depression is loss of appetite, which is often associated with symptoms such as dyspnea and nausea but also with side effects of standard drug therapy for HF (such as digoxin, angiotensin-converting enzyme inhibitors, beta-blockers, and diuretics). Patients with severe HF often suffer from intestinal edema associated with loss of taste, nausea, and gastrointestinal disorders, which can lead to loss of appetite and malabsorption [34]. It is worth noting that the gut microbiota, which is known as the “second largest genome”, is widely involved in nutrient absorption, regulating intestinal epithelial function and influencing local or systemic immune inflammatory responses in the intestine; intestinal metabolites can also be released into the blood to play a systemic regulatory role [35]. In addition, blood redistribution and depression in patients with HF can lead to the upregulation of zonulin 2 precursor expression and the downregulation of zonula occludens-1 (ZO-1) expression, resulting in increased intestinal permeability and impaired intestinal epithelial barrier function. This could, in turn, lead to bacterial translocation and endotoxin release into the blood, further aggravating cardiomyocyte and myocyte injury [36]. It is worth noting that loss of appetite is a long-standing problem, and fatigue, depressive symptoms, and low quality of life are independent predictors of appetite decline over time [37].

The proteasome is a protein complex that labels and degrades unwanted or damaged proteins with the help of a small protein called ubiquitin. The entire system of ubiquitination and proteasome degradation is known as the ubiquitin–proteasome system (UPS). Excessive activation of the UPS leads to increased proteolytic metabolism, resulting in an imbalance in myogenic fibronectin levels and causing muscle atrophy [38]. Monoubiquitinated target proteins are degraded by lysosomes, whereas the degradation of target proteins by UPS requires polyubiquitination. E3 ubiquitin–protein ligase is the rate-limiting enzyme for the polyubiquitination of protein substrates, and its most relevant to sarcopenia are tripartite motif-containing 63 (TRIM63) and F-box only protein 32 (FBXO32) [39, 40, 41]. TRIM63 and FBXO32 are mainly regulated by the transcription factors nuclear factor-$\kappa$B (NF-$\kappa$B) and forkhead box O (FOXO) protein family [42]. Activated NF-$\kappa$B and FOXO, in turn, are mainly induced by proinflammatory cytokines, such as tumor necrosis factor (TNF), which is often highly expressed in patients with HF [43].

Autophagy is another important mechanism of sarcopenia in which the lysosomal protease histone L plays a major role. Under normal conditions, autophagy is considered to be a nonselective degradation pathway of unnecessary or nonfunctional cellular components, such as damaged organelles and protein polymers [44]. Thus, autophagy under physiological conditions plays a significant role in maintaining normal muscle function. However, excessive autophagy exacerbates muscle atrophy, and excessive accumulation of autophagic vesicles occurs in almost all myopathies. Autophagy is usually increased through the FOXO and adenosine monophosphate-dependent protein kinase pathways, leading to myofiber atrophy. Studies have demonstrated that both UPS and autophagy are induced in the skeletal muscle early in the course of HF [45]. The above suggests that although autophagy is involved in the maintenance of muscle function, it may be detrimental when induced under catabolic conditions.

HF is a disease characterized by chronic low-level inflammation. Inflammation not only affects cardiovascular function but also has a persistent effect on the skeletal muscle. Furthermore, chronic inflammation is thought to be associated with the pathogenesis of depression, with inflammation and inflammatory diseases causing mood disorders and poor mental health [46]. A cross-sectional study by Visser et al. [47] demonstrated that high levels of interleukin 6 (IL-6) and TNF-$\alpha$ in elderly people are associated with lower muscle mass and strength. In addition, a prospective study on inflammation and muscle strength by Schaap et al. [48] indicated that the risk of muscle strength loss in elderly people was associated with high levels of IL-6 and C-reactive protein (CRP), suggesting that some inflammatory factors are directly involved in the pathogenesis of sarcopenia. The above inflammatory factors can induce apoptosis, enhance protein hydrolysis and inhibit muscle structural protein gene transcription. Inflammatory cytokines can further activate UPS and induce anorexia and lipolysis, leading to sarcopenia and even cachexia [49]. In addition, HF and depression, which lead to reduced exercise and a sedentary lifestyle, can induce inflammation in the body, releasing inflammatory mediators that destroy the muscle structure and exacerbate fat accumulation, causing the muscle strength to decrease and further promoting reduced activity, thus forming a vicious cycle [50].

The abnormal release of reactive oxygen species (ROS) due to oxidative stress (OS) is a major cause of cellular senescence and apoptosis and often manifests as metabolic abnormalities. OS is extensively involved in diseases associated with aging, including sarcopenia and HF [51]. Studies have demonstrated elevated levels of OS-related markers in patients with HF and an association with reduced exercise tolerance and poor prognosis, which may be related to the high rate of anaerobic metabolism imposed on the organism by a low cardiac output and skeletal muscle hypoxia due to endothelial dysfunction [52]. In addition, excessive ROS can lead to mitochondrial dysfunction, which results in cytochrome c release and activation of caspase 3 and caspase 9, accelerating skeletal muscle injury and degeneration, especially by disrupting the excitation–contraction coupling structure of the muscle [53, 54].

Cardiac and skeletal myocytes could secrete different myokines that are released into the circulation in an autocrine, paracrine, or endocrine manner to regulate the body’s energy metabolism, insulin sensitivity, lipolysis, free fatty acid oxidation and glycogen metabolism [55]. Myostatin have been shown to be elevated in skeletal muscle in patients with HFpEF or HFrEF [27]. Some of the myokines exert metabolic regulatory effects related to the prevention of cardiovascular diseases, such as myostatin, irisin, apelin, and brain-derived neurotrophic factor (BDNF) [56]. Myostatin, also known as growth differentiation factor 8 (GDF8), is a member of the transforming growth factor $\beta$ (TGF $\beta$) protein family, a class of proteins produced and released by myocytes that inhibit myocyte growth [57]. Studies have demonstrated that myostatin plays a key role in the regulation of skeletal muscle mass and cardiac muscle mass. The activation of the myostatin precursor complex promotes myostatin binding to activin receptor type IIB (ActRIIB) on myofibrils, and downstream mediators cause decapentaplegic homolog 2 (SMAD2) and decapentaplegic homolog 3 (SMAD3) phosphorylation and also affect the corresponding gene transcription [58]. Elevated levels of myostatin have also been observed in HF. Although myostatin may exert some antimyocardial hypertrophic effect, it also promotes myocardial fibrosis [59]. Irisin is produced in large amounts in cardiac and skeletal muscle and protects the myocardium from ischemia-reperfusion injury. Irisin is also involved in central and peripheral neurogenesis [60]. Apelin is associated with the induction of mitochondrial production, which reduces inflammation, stimulates regenerative capacity, and avoids age-related muscle atrophy. Apelin is also involved in physiological processes such as metabolism, cardiac contraction, angiogenesis, and blood pressure regulation [61]. Studies have shown that increased levels of BDNF are detected in human skeletal muscle after exercise. Specifically, tropomyosin receptor kinase B (TrkB) protects against myocardial repair through dimerization with BDNF and intracellular kinase-specific tyrosine phosphorylation, ultimately enhancing the proliferation and survival of cardiac microvascular endothelial cells [56].

Ghrelin expressed in the gastric fundus stimulates the secretion of growth hormone (GH), cortisol, aldosterone, catecholamines and prolactin [62]. The body’s anabolic and catabolic activities are closely related to the aforementioned hormones. For example, ghrelin induces the secretion of GH, which, in turn, exerts anabolic effects directly or indirectly through insulin-like growth factors. Plasma ghrelin levels reflect the nutritional status of the individual and the level of body fat storage. Ghrelin has been found to be significantly increased in patients with cardiac cachexia [63].

Insulin-like growth factor 1 (IGF-1) is a hormone with a molecular structure similar to that of insulin and plays an important anabolic role in the adult body [64]. Contrarily, diminished IGF-1 function is an important component of the sarcopenia process and is not associated with the downregulation of IGF-1 or IGF-1 receptor expression [65]. Mechanistically, upon binding of IGF-1 to its receptor, insulin receptor substrate 1 (IRS1) is activated by phosphorylation and subsequently activates the phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB/AKT)-mammalian target of rapamycin (mTOR) signaling pathway. The PI3K-AKT-mTOR pathway inhibits FOXO and glycogen-synthase kinase 3 (GSK3) and suppresses the activation of SMAD2 by myostatin, leading to increased protein synthesis [66]. Moreover, GH facilitates amino acid delivery to the skeletal muscle and inhibits protein hydrolysis via downstream signaling from IGF-1. However, the number of GH receptors decreases with age, and GH deficiency and lower levels of IGF-1 are associated with an increased risk of endothelial dysfunction and cardiovascular events [67]. In addition, Gold et al. [68] found increased secretion of corticotropin-releasing hormone (CRH) in depressed patients, which leads to increased secretion of epinephrine and norepinephrine in the body and induces an inflammatory response. Epinephrine and norepinephrine can lead to endothelial dysfunction, blood flow heterogeneity, and reduced capillary density, which are associated with the development of sarcopenia [69].

Patients with depression have sedentary lifestyles. A retrospective study by Burton et al. [70] demonstrated that depressed patients exhibited reduced daytime activity compared with healthy controls. Patients with HF also show a lack of exercise due to physical limitations. From a neurological point of view, physical inactivity also means a reduction in the activity of motor units. Unused or rarely used neurons undergo disuse degeneration, which, in turn, leads to further disuse degeneration of their synaptic junctional cells [71]. Thus, physical inactivity due to disease or sedentary behavior can cause disuse atrophy of the muscles.

In addition, the skeletal muscle is composed of different types of fibers. Among them, type I fibers are rich in mitochondria, muscle protein content and associated capillaries and have low ATPase, creatine kinase and glycolytic activities. Therefore, type I fibers efficiently use oxygen for sustained and slow muscle contraction [72, 73]. Contrarily, type II fibers have high ATPase, creatine kinase and anaerobic glycolytic activity, so type II fibers primarily use anaerobic metabolism for rapid contraction [74]. Muscle fiber types can change in response to external stimulation. Aging-induced loss of peripheral motor neurons, reduced number of motor units, altered neuromuscular connectivity and selective denervation of type II fibers all lead to atrophy of fast-contracting type II fibers [75]. Contrarily, the fiber-type shift in patients with severe HF tends to occur before muscle atrophy, with a lower percentage of type I fibers and a higher percentage of type II fibers [76]. In addition, apoptosis of the skeletal muscle cells correlates with the severity of HF and is accompanied by decreased levels of the antiapoptotic factor B-cell lymphoma 2 (BCL-2) and increased levels of the pro-apoptotic factor BCL-2-associated X protein (BAX) [77].

Aging is strongly associated with impairments in cardiovascular function, muscle strength and cognitive performance. Mechanistically, aging- associated mitochondrial dysfunction, decreased levels of protein synthesis and peroxisome proliferator-activated receptor $\gamma$ coactivator 1-$\alpha$ (PGC1-$\alpha$), as well as protein degradation, muscle atrophy and denervation, and a shift in energy metabolism to anaerobic metabolism all increase the risk of cardiomyopathy and other cardiovascular complications [78, 79].

In patients with HF, decreased skeletal muscle blood flow due to reduced cardiac output affects the oxygen supply to that organ, which leads to decreased muscle function. The skeletal muscle is an important organ of the body involved in glucose metabolism, and reduced muscle mass affects glucose homeostasis in the body. Several studies have revealed a relationship between blood glucose and depressive symptoms [80, 81].

In addition, visceral fat accumulation is a risk factor for chronic degenerative diseases, such as cardiovascular disease, dementia and depression. Another morphological aspect of aging skeletal muscle is the infiltration of fat into muscle tissue components. Fat can be contained in both adipocytes and deposited in muscle fibers, which is an important factor contributing to reduced blood flow and decreased muscle mass [82]. Patients with sarcopenia may be involved in muscle loss due to increased adipose tissue through increased proinflammatory cytokines and decreased release of muscle factors, leading to the development of cardiovascular disease [83].

Both HF and sarcopenia are associated with anorexia, and patients with both conditions have low scores in nutritional assessment, suggesting that patients with HF and sarcopenia are more predisposed to malnutrition [85]. In addition, although nutritional assessment is currently performed less frequently in patients with depression, the pathogenesis of nutritional status of patients with depression remains unclear [28]. Similarly, anorexia nervosa is very common in patients with cachexia. Although cachexia cannot be reversed by improving nutritional intake, the beneficial effects may be achieved by increasing calorie, protein, or amino acid intake [14]. Saitoh et al. [86] have showed that Inflammation, use of loop diuretics, and cachexia are associated with an increased likelihood of anorexia in patients with HF, and patients with anorexia showed impaired functional capacity and poor outcomes. Some scholars have suggested that all patients with HF should take micronutrient supplements and avoid excess salt ($\le$6 g/day) and fluids ($\le$2 L/day) [14]. However, a recently published article showed no effect of dietary intervention to reduce salt intake [87]. Thus, the current recommendation of avoiding excess salt needs to be critically proofed and clinical randomized trials are needed further. While a high-calorie, protein-rich nutritional structure has shown benefit in cachectic patients, essential amino acids (especially branched-chain amino acids) may be more beneficial to patients with sarcopenia. Cheese, whey protein, leucine, and vitamin D have been studied and shown to improve muscle mass in the elderly [14, 88, 89].

Exercise training is a nonpharmacological, low-cost, effective and safe treatment that is capable of improving depressive symptoms regardless of the patient’s psychiatric diagnosis, which makes it an excellent treatment strategy for depression [95]. Aerobic exercise activates peroxisome proliferator-activated PGC1-$\alpha$, which induces mitochondrial biogenesis and inhibits the formation of FOXO3, a key protein for proteolysis [96]. In addition, anaerobic exercise also increases IGF-1 production by stimulating the PI3K/AKT pathway to stimulate myogenic fibronectin production [97]. The above processes further enhance protein synthesis and inhibits FOXO3 through AKT-mediated phosphorylation, thereby delaying sarcopenia [97]. Although a study assessing the effect of regular physical activity on local inflammatory parameters in skeletal muscle in patients with chronic heart failure (CHF) showed that aerobic training did not alter serum TNF, IL-1$\beta$, or IL-6 levels [98], it significantly reduced the levels of these cytokines and nitric oxide synthase in the skeletal muscle. Notably, aerobic training resulted in a 33% reduction in TRIM63 expression in patients with HF aged 55 years. This result was even more pronounced in the HF population aged $>$65 years (37% reduction in TRIM63 expression), suggesting that exercise training blocks the activation of UPS in patients with HF independently of age [99]. Meanwhile, patients with HF who underwent 12 weeks of exercise training exhibited a 36% reduction in local myostatin mRNA expression levels, although the serum myostatin expression was not altered, demonstrating the powerful therapeutic effect of exercise on sarcopenia [100].

Regular and appropriate physical activity can promote physical and mental health. As demonstrated in the HF-ACTION study, exercise can moderately reduce depressive symptoms in patients with HF [101]. However, excessive exercise can lead to emotional instability, reduce the body’s immunity, and affect physical health [102, 103]. Regular aerobic exercise that causes mild or moderate shortness of breath is recommended for patients in the ESC guidelines (Class I, Level A evidence) [2]. Similarly, regular physical activity is recommended in the ACC/AHA guidelines as a safe and effective way of improving body function (Class I, Level A evidence) [1]. Resistance exercise training may be a good strategy to improve the muscle structure in patients with sarcopenia. A randomized controlled trial revealed that after a 10-week period of high-intensity resistance training performed three times a week, patients exhibited an increase in muscle strength and endurance [104]. Also, Tieland et al. [105] found that protein supplementation combined with resistance exercise training for 24 weeks resulted in significant improvements in muscle mass and strength, suggesting that nutritional supplementation combined with exercise therapy may be more efficient.

A large number of medications may be beneficial to patients with HF and wasting. Potential drugs include anabolic steroids, anti-myostatin antibodies and ghrelin receptor agonists (such as anamorelin), anti-inflammatory drugs, appetite enhancers, proteasome inhibitors, and beta-adrenergic agonists.