Cardiac and Cancer-Associated Cachexia: Role of Exercise Training, Non-coding RNAs, and Future Perspectives

Abstract

Sarcopenia has been defined as the loss of skeletal muscle mass and strength that occurs with advancing age and has also been related to many metabolic diseases. In late stages, sarcopenia precedes cachexia, defined as a multifactorial syndrome characterized by an ongoing skeletal muscle wasting, with or without loss of fat mass, associated with poor prognosis in diseases, worsening quality of life and survival. Heart failure and cancer-associated cachexia represents a progressive involuntary weight loss and is mainly the result of an imbalance in the muscle protein synthesis and degradation, inflammation, and oxidative stress, causing muscle wasting. Importantly, both diseases are still the main causes of death worldwide and the molecular basis of cachexia is still poorly understood. Recently, non-coding RNAs have been described to regulate the cardiac and cancer-associated cachexia. On the other hand, exercise training is a promising ally in slowing down cachexia and improving the quality of life of patients. New studies demonstrate that exercise training, acting through non-coding RNAs, may be able to mitigate muscle wasting, as protein turnover, mitochondrial biogenesis, and antioxidant capacity improvement. This review will therefore discuss the molecular mechanisms associated with the muscle wasting in both cardiac and cancer cachexia, as well as highlighting the effects of exercise training in attenuating the loss of muscle mass in these specific conditions.

1. Introduction

Cardiovascular diseases (CVD) and cancer (CA) are the two leading causes of death worldwide, representing about 28 million deaths per year [1, 2, 3, 4]. Only CVDs affected 523 million cases worldwide, representing the main cause with 18 million deaths each year [4]. Currently, CA is the second disease in the number of deaths in the world, but its prevalence has been increasing in recent years and, in some countries, it is the main cause of death [5]. GLOBOCAN data show that in 2021, 19.3 million new cases and 10 million deaths from the CA disease were reported [6]. Considering the worldwide increase in the prevalence of CA and the high mortality from CVD, both diseases represent a serious public health problem.

The heart failure (HF) is the final common pathway of most cardiac and circulatory diseases [7]. The American Heart Association (AHA) defined HF as clinical syndrome characterized by typical symptoms such as edema, dyspnea, and fatigue; caused by changes in cardiac function and structure, with reduced cardiac contraction and/or increased intraventricular pressure at rest and physical stress [7, 8, 9]. In addition to central cardiac alterations, HF promotes changes in peripheral structure and function, impairing oxidative metabolism accompanied by microvascular rarefaction and skeletal muscle wasting [8, 10, 11, 12]. These changes in skeletal muscles contribute to reduced quality of life and increased mortality. Worldwide, HF affects more than 23 million people [7, 9], and just in the United States, around 6 million American citizens are affected, leading to more than 1 million hospitalizations/year and a mortality rate of 1 in every 9 patients hospitalized [2]. Furthermore, worsen projections are expected for the next 10 years, with an increase of 46% in cases, generating an estimated annual expenditure of 70 billion dollars, making a health epidemic [2, 13, 14].

In CA, studies have been shown that is a group of diseases characterized by uncontrolled cell growth, spreading and progressing to other cells beyond physiological limits, affecting any organ and tissue in the human body [1]. In 2021, 2.2 million new cases of breast CA have been reported worldwide, thus being the most prevalent, followed by lung CA (2.1 million), colon and rectum (1.8 million), and prostate (1.3 million). Regarding mortality, lung CA is the most lethal in the world followed by breast CA [15, 16].

Even with new drugs and therapies, there is still an increase in the prevalence of both diseases [6, 17]. Furthermore, the progression of HF and CA is related to muscle wasting and loss of body weight as well as consequent weakness toward to important clinical consequences in these diseases [18, 19]. Numerous studies demonstrate that involuntary body weight reduction, with increased muscle wasting, is the main sign of cachexia, represented by a multifactorial syndrome related to pre-established chronic diseases [18, 20]. Currently, in the world, 12 million patients have cachexia, which is responsible for worsting prognoses on established diseases, reduced quality of life, impaired therapeutic effectiveness, and increased mortality [21, 22].

To date, there are no effective pharmacological treatments for cachexia for both HF and CA [17, 23]. On the other hand, exercise training (ET) is a non-pharmacological treatment, relatively cheap and safe. In addition, ET promotes anabolic stimuli, which may preserve the muscle wasting, and at the same time enhance the quality of life and reduce mortality in cachexia patient [18, 24, 25]. During the last decades, the class of non-coding RNAs (ncRNAs): microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) have been demonstrating important associations with CVD, CA [26, 27], and with the muscle wasting promoted by cachexia [28, 29], becoming a promising mechanism to the understanding cardiac and CA cachexia.

Although great advances have been made to understand HF and CA, the mechanisms involved in skeletal muscle abnormalities, still poorly understood [3, 12, 15, 30, 31]. Therefore, understanding the mechanisms and pathways involved in skeletal muscle structure and function may help to develop new therapeutic strategies against cachexia, resulting in improved treatment and quality of life for patients [20, 32]. Consequently, this review aims to discuss the molecular mechanisms, involving ncRNAs in cardiac and CA cachexia. In addition, to known the implication of ET and ncRNAs in the treatment of cachexia.

2. Cachexia in heart failure and cancer

Cachexia (from the Greek ‘kakos’ for bad, and ‘hexis’ for condition) was first described, as a result of chronic disease, in 1860 by the French physician Charles Mauriac, which consider only as muscle disease, close to a metabolic syndrome [25, 33, 34]. Over the years, the term cachexia has been updated and nowadays is considered as a multifactorial syndrome characterized by loss of appetite, body weight (with significant muscle wasting), which may or not extend to adipose tissue. The advancement of cachexia decreases muscle function, worse fatigue, and reduces the quality of life and life expectancy of patients [21, 25, 35]. Also, recent studies demonstrate that cachexia can communicate with multiple organs, such as the heart, adipose tissue, intestine, kidneys, and liver, helping the development and progression of disease [31, 36].

Among the chronic diseases that commonly progress to cachexia, HF and CA have the largest number of affected patients [37]. Anker et al. [38] were the first authors to describe muscle wasting in HF patients, where patients with reduced body weight were diagnosed with cardiac cachexia. In 2012, the European Society of Cardiology (ESC) recognized cachexia as a comorbidity of HF [39] and in 2016 the ESC began to recommend the non-reduction of body weight in HF for obese or overweight patients [40]. In HF, the involuntary loss of body weight is considered an independent factor to reduce physical capacity, and poorer quality of life [38, 41].

The cardiac cachexia prognosis is extremely complex, with annual mortality about 20 to 40%, reaching up to 50% of patients death after 18 months of diagnosis [37, 38]. On the other hand, the cardiac cachexia incidence can range from 10–39%, depending on study design and HF patients prognosis [42, 43]. In the SICA-HF study (studies investigating co-morbidities aggravating HF), investigated cardiac caquexia in 207 HF patients with reduced ejection fraction (HFrEF) and preserved (HFpEF), of these 21% had cachexia independent of ejection fraction [44]. Studies show that cardiac cachexia would be more present in patients with HFrEF, being associated with a 3-fold higher risk of death from all causes compared to those with HFpEF [38]. On the other hand, implications of cardiac cachexia in patients with HFpEF still need further studies [42]. Valentova et al. [42], based on their clinical experience, reported that patients with HFpEF shows cardiac cachexia signs only in advanced stages of HF, possibly acting in a different biological pathway in the development of the disease [45].

Numerous changes between central and peripheral organs were observed in patients with HF [46], followed by abnormalities in skeletal muscle such as capillary rarefaction, type I to II fiber switch, impaired oxidative metabolism, decreased excitation-contraction coupling, and muscle atrophy [47, 48]. In general, cardiac cachexia is responsible for muscle atrophy in the early stages of the disease and may progress to loss of adipose tissue, just in the late stages of the disease [42]. Regarding myocardial impairment in cardiac cachexia, more solid data are needed to help distinguish the structural and functional changes related to cardiac disease from those found in cardiac cachexia. Currently, contradictory data demonstrate cardiomyocytes wasting with or without cardiac impairment [22, 49]. It is necessary to emphasize to achieve correct values of cardiac cachexia it is necessary to exclude edema values from the total body weight, a difficult task for patients with HF that hinders the accurate diagnosis of cardiac cachexia [32].

In CA, depending on the stage and development of the disease, 80% of patients have cachexia, leading to death of 30% of these patients [15, 50]. Fearon et al. [51] classifies CA cachexia into 3 stages: pre-cachexia, cachexia, and refractory cachexia. It is necessary to understand that not all patients will go through the three stages. Then, the type and stage of CA can influence the progression of cachexia, as well as systemic inflammation, low food intake. In addition, CA cachexia can reduce tolerance to responses to chemotherapy treatments, worsening the prognosis of patients [50, 52].

Regarding the incidence of CA cachexia, the type of cancer may influence, since patients with gastric or pancreatic CA have over 80% of incidence. On the other hand, patients with lung, prostate, or colon CA have an incidence of 50%, and 40% of patients with advanced breast, head, and neck tumors and some leukemias develop the syndrome [35, 53, 54].

Both cardiac and CA cachexia share symptoms, as described in Figure 1, but cardiac cachexia presents a slower and more gradual muscle wasting [55] when compared to CA, with a progressive and rapid muscle wasting, leading to earlier death compared to cachexia from cardiac causes [56]. The international consensus for the diagnosis of cachexia is similar between HF and AC, namely: body weight loss >5% or > 2% in individuals with low BMI (< 20 kg/m²) or loss of skeletal muscle mass in 12 months [31, 51].

Figure 1.

Common symptoms of cardiac and cancer cachexia.

3. Non-coding RNAs in cardiac and cancer cachexia

Several factors are involved to cardiac and CA cachexia like imbalance between protein synthesis and degradation, high inflammatory levels, and metabolic dysfunction (Figure 2). However, the pathophysiological mechanisms involved in muscle wasting induced by cardiac and CA cachexia are not fully understood. Thus, in recent years, researchers have been identifying a set of ncRNAs, with great regulatory potential in skeletal muscle, and that may have important roles in controlling muscle wasting in cachexia [29, 57].

Figure 2.

Factors contributing to cardiac and cancer cachexia and the role of exercise in reversing these damages.

ncRNAs are RNA molecules not translated into proteins, organized in classes depending on their structure. miRNAs have approximately 19–25 nucleotides (nt) and play a regulatory function in gene expression, through translation inhibition of messenger RNA (mRNA). The lncRNAs have approximately 200 nt in their composition and primarily interact with mRNA, DNA, protein, and miRNA and consequently regulate gene expression at the epigenetic, transcriptional, post-transcriptional, translational, and post-translational levels in a variety of ways. CircRNAs is produced by the circularization of specific exons by covalently linking the 3′ end of one exon to the 5′ end of another. It is known to function as a kind of miRNA sponge, thus regulating transcription, splicing, and production of peptides by translation [58, 59].

Among the ncRNAs, miRNAs have been the most studied to date due to be essential to numerous cellular functions, from fetal formation to disease development [59, 60]. miRNAs are expressed in all body tissues, but in skeletal muscle, 25% of all expressed are muscle-specific, and play important roles on muscle mass and homeostasis [29, 61]. These muscle-specific miRNAs are termed “myomiRs”, and include miRNA-1, −133a, −133b, −206, −208a, −208b, −486, and − 499. Because myomiRs are exclusively expressed or enriched in striated muscle (skeletal muscle and cardiac), they occupy essential functions in the regulatory networks of myogenesis, fiber type composition, muscle growth, and metabolism [60, 61, 62, 63, 64]. Beyond the myomiRs, some miRNAs (e.g., miRNA-21, −24, −29b, −199, −214) shows important roles in atrophy, especially in cachexia, and known as “atromiRs” [57, 63].

Both lncRNAs and circRNAs shows important regulation on skeletal muscle and diseases such as HF and CA [29, 59, 65, 66]. Professor Chen’s group, in recent years, has been investigating the lncRNAs on the molecular mechanisms of skeletal muscle mass development and control. In their works, it was found more than 4,400 lncRNAs related to atrophy mechanisms in C2C12 cells (i.e., myoblasts) [67, 68]. In the same way, circRNAs have also been related to the development and control of skeletal muscle mass [65, 68]. Although ncRNAs have a promising future, further research is needed to better understand the ncRNAs on muscle wasting mechanisms in cardiac and CA cachexia. Thus, the next topics presents the new perspectives of ncRNAs in cardiac and CA cachexia.

3.1 Cardiac cachexia and non-coding RNAs

Currently, ncRNAs are associated with molecular mechanisms in HF, responsible for progression, treatment, and use as biomarkers of the disease [59, 69, 70]. On the other hand, studies involving muscle wasting, ncRNAs, and HF remain rare. Moraes et al. [71] was the first group to investigate cardiac cachexia and ncRNAs. The study identified several changes in the regulatory pathways, such as cellular matrix, protein degradation, metabolism, c-Jun N-terminal kinase (JNK) cascade, and cellular response to the transforming growth factor-beta (TGF-β) in soleus muscle from cardiac cachexia animal. Indeed, the cellular responses found are close to those have found in patients with cardiac cachexia [24]. Furthermore, the authors demonstrated 18 differentially expressed miRNAs, where 5 was down-regulated (miRNA-30d, −146b, −214, −489 and − 632) and 13 was up-regulated (miRNA-27a, −29a, −29b, − 132, −136, −204, −210, −322, 331, −337, −376c, −434 and − 539). After gene ontology analysis, all miRNAs showed enriched to the muscle mass control pathway (Figure 3) [71]. However, most of the reported miRNAs were different from those usually found in skeletal muscle atrophies (e.i., induced by other etiologies, such as dystrophies, diabetes, and denervation) [72, 73], but they were close to those altered in HF and cardiac remodeling [71]; suggesting a unique profile of miRNAs responsible for muscle wasting in cardiac cachexia.

Figure 3.

Non-coding RNAs involved in cardiac and cancer cachexia.

In HF, most miRNAs were found differentially expressed in both heart and skeletal muscle [63]. Moreover, many of these miRNAs are also found in blood circulation, probably allowing myocardium-skeletal muscle cross-talking, through miRNAs circulating between tissues. This communication is not exclusive to miRNAs, but it is common to all ncRNAs through lipid vesicles or proteins (e.g., exosomes) [59]. In fact, cell culture experiments have already shown that distinct cells such as cardiac fibroblasts, endothelial cells, cardiomyocytes, myoblasts, and myotubes can communicate with each other through exosomes-miRNAs [74, 75]. Therefore, during cardiac cachexia, muscle wasting probably is influenced by other tissues, such as the myocardium, through miRNAs leading to molecular changes in cachexia development [63]. In conclusion, myocardium-skeletal muscle communication via miRNAs still needs better investigation, but it sets a great precedent to understand the role of miRNAs in HF-derived dysfunctions and cardiac cachexia.

Although lncRNAs and circRNAs are not fully understood in the context of cardiac cachexia, preliminary studies have been shown a regulatory potential in the development of HF [59, 66], and skeletal muscle regulation [29, 65].

As seen above, muscle wasting in cardiac cachexia patients is an important limiting factor in daily activities and quality of life [25]. Muscle wasting is a consequence of imbalance of synthesis, and degradation protein [76]. In the last years, cardiac cachexia studies have focused on the ubiquitin-proteasome (UPP) and autophagy/lysosomal proteolytic pathways to understand the muscle wasting process [57, 77, 78, 79]. The UPP plays an important role in the breakdown of myofibrillar proteins in cardiac cachexia [80]. Proteolytic activity, through the UPP, depends on the limited expression of enzymes, which include the E3 ubiquitin-ligases muscle RING finger 1 (MurRF1) and muscle atrophy F-box (atrogin-1). The expression of these enzymes is determined by transcription factors such as the forkhead box O (FOXO) family [25, 57]. The increased expression of miRNA-18a up-regulate atrogin-1 and MuRF-1 expression; otherwise, reduced expression of miRNA-18a down-regulates FOXO3 expression, controlling myotube hypertrophy [81]. miRNA-29 plays a central role in cachexia, affecting protein synthesis and degradation pathways [57]. The increased expression of miRNA-29b led to muscle wasting with high expression of MuRF-1 and atrogin-1 and genes involved in autophagy [57]. The miRNA-23a antagomiR administration, an oligonucleotide, which acts as a competitive inhibitor of miRNA-23a, increased the expression of MuRF-1, revealing itself as an important negative regulator of the UPP [82].

The lncRNA HOX Transcript Antisense RNA (HOTAIR) can assume epigenetic functions, binding to E3 ubiquitin-ligases facilitating protein degradation through the UPP [83]. Also, the lncRNA cardiac hypertrophy-associated transcript (Chest) may regulate autophagy helping cardiomyocyte hypertrophy, and its expression was found to be increased in cardiac disease patients [84]. CircNfix is a key circRNA in cardiac muscle regeneration and regulation, whereas reducing circNfix expression promotes cell proliferation, angiogenesis, and reduced cell death [85]. CircNfix promotes the interaction of Ybx1, a transcription factor related to cell proliferation, and Nedd41, an E3 ubiquitin-ligases. Additionally, circNfix acts as a miRNA-214 sponge to promote glycogen synthase 3-β (GSK-3β) expression, a protein synthesis pathway inhibitor [85].

Protein synthesis is also essential to maintain skeletal muscle during HF [76, 86, 87]. The stimulation of phosphoinositide 3-kinase-serine/serine–threonine protein kinase (PI3K/Akt) pathway is stimulated by the insulin-like growth factor 1 (IGF-1), leading to an increase in activation of mammalian target of rapamycin (mTOR) [88]. The IGF-1/PI3K/Akt/mTOR pathway is the major signaling pathway known in skeletal muscle protein synthesis control [89, 90]. Indeed, mTOR activation-induced protein synthesis, allowing complex signals, such as TORC1 activating the ribosomal protein S6 kinase (p70S6k) and eukaryotic translation initiation factor 4E-Binding protein 1 (4E-BP1) pathways and TORC2 controlling the autophagy process [79, 91]. In cardiac cachexia, IGF-1 is down-regulated, promoting lower protein synthesis and increased degradation, aiding in muscle wasting [25].

The myomiRs-1 and -133a participate in several roles in cell development, differentiation, and growth. Besides, both have been validated to target IGF-1 [92, 93, 94], and reduction in both expression induces skeletal muscle hypertrophy [74, 95, 96]. On the other hand, increased expression of miRNA-1 and -133a can lead to muscle atrophy [63]. The binding of IGF-1 to its receptor, insulin receptor substrate 1 (IRS-1), active, through its own phosphorylation, the PI3K/AKT/mTOR signaling pathway [25]. In this way, miRNA-378 performs an important anti-hypertrophic role, acting as an inhibitor of IRS-1 via AMP-activated protein kinase (AMPK) signaling [97]. Furthermore, the miRNA-1 low expression in HF muscle patients reduce the protein expression of phosphatase and tensin homolog (PTEN), an important protein in the regulation of the synthesis pathway [98]. Bioinformatics analyzes demonstrated that miRNA-22 expression target PTEN and Sirtuin 1 protein, both responsible to regulate hypertrophy in cardiomyocytes [99, 100]. On the other hand, the synthesis pathway inhibits the FOXO family and GSK-3β leading to increased protein synthesis [25]. In HF animal models, the increase in miRNA-29 expression regulates the function of GSK-3 β, preventing hypertrophy via the nuclear factor of activated T cell (NFAT) [101]. Likewise, the miRNA-29 down-regulation leads to muscle atrophy in C2C12 cells and in cardiac cachexia patients [71]. The miRNA-23a, −132 and − 212 are related to the suppression of FOXO3, the main isoform of the FOXO family, responsible for the regulation of protein synthesis [102, 103].

Although the CircRNA SLC8A1–1 (circSLC8A1–1) has not been observed in HF yet, the circRNA expression is directly related to hypertrophy, acting as a sponge for miRNA-133 [94]. Another circRNA identified as HRCR was the first circRNA related to cardiac hypertrophy, and it is down-regulated in cardiac hypertrophy animal models, while miRNA-223 expression was increased. HRCR acts as a sponge for miRNA-223 controlling hypertrophy [104]. The muscle wasting mechanisms in cardiac cachexia are complex, and not fully understood. At the moment, ncRNAs seem to be indispensable. However, ncRNAs constitute a diverse class of molecules capable act in gene expression and skeletal muscle homeostasis. In cachexia, many of these ncRNAs are differently expressed, imply functional changes, and aggravate the progression of the disease. Further studies are needed to better understand the pathophysiological mechanisms of cardiac cachexia under ncRNAs participation.

3.2 Cancer cachexia and non-coding RNAs

In silico and in vivo approaches demonstrated the involvement of miRNAs-21 and -206 in the regulation of muscle wasting from different atrophic models (i.e. diabetes, cancer cachexia, chronic renal failure, fasting, and denervation) by targeting the transcription factor YY1 and the translational initiator factor eIF4E3, indicating these miRNAs as fine-tuning regulators from muscle catabolism [73]. The tumor-secreted miRNA-21 and -29a showed an activation of premetastatic inflammatory pathways, mediated by its binding to the Toll Like Receptor (TLR), such as, murine TLR7 and human TLR8. CA-induced miRNA-21 was also found to be overexpressed in exosomes during tumor evolution, which signals through the TLR7 on myoblasts to promote cell apoptosis [105, 106].

A recent meta-analysis showed that miRNAs are related to muscle wasting during CA cachexia, including miRNAs-27a, −27b, −140 and -199a. These miRNAs favor atrophy and also inhibit muscle growth [107].

In studies using wild-type mice and poly (ADP-ribose) polymerases- 1(Parp-1) ⁻/⁻ and Parp-2 ⁻/⁻ with Lewis lung carcinoma revealed that the miRNA-1 was found down-regulated in the skeletal muscle of these animals. Furthermore, miRNA-133a was reduced in the diaphragm and gastrocnemius of animals with Parp-2 ⁻/⁻, while animals with Parp-1 ⁻/⁻ showed difference only in the reduction of the diaphragm. The expression of miRNA-206 and -486 in tumor bearing-mice was also lower in wild-type animals. There was proliferation and differentiation of muscle cells in Parp-1 ⁻/⁻ mice via miRNA-133a, −206, and − 486 action, while the inhibition of Parp-2 through miRNA-206 promoted the differentiation of muscle cells in the gastrocnemius muscle [108].

Lee et al. [109] performed analysis in CA cachectic mice whereas they found 9 differentially expressed miRNAs, namely: miRNA-147, −205, −223, −299a, −431, −511, −665, −1933 and -3473d, most of all involved in many functions, such as cell growth, signaling, inflammatory response, and catabolism [109]. In another study, with CA cachexia patients, 5 miRNAs were found differently expressed. Of these, miRNA-23a, −99b, −483 and − 744 were down-regulated, and miRNA-378 was up-regulated in these patients and were involved with catecholamine-stimulated lipolysis in adipocytes [110].

Patients with CA cachexia showed up-regulation of 8 miRNAs, which were involved in myogenesis, muscle metabolism and inflammation (miRNAs-let-7d, −199a, −345, −423, −532, −1296 and − 3184) [111]. A study using vastus lateralis biopsy showed a higher expression of miRNA-424, and -450a and a lower expression of miRNA-144 and -451a. These processes involved target genes related to IL-6, TGF-β, TNFα, insulin and Akt pathway, thus contributing to a reduction in the survival of these patients [112].

Regarding lncRNAs in cachectic animals, lncIRS1 was described to act as a sponge for miRNA-15, regulating the expression of IRS1. When this lncRNA is overexpressed, it activates the signaling pathways IGF-1 / PI3K / Akt, thus increasing protein synthesis. Furthermore, this increase in its expression inhibits muscle wasting. When suppressed, there is a decrease in IGF-1 levels in favor to muscle wasting [113]. LncRNA muscle anabolic regulator 1 (MAR1) showed an interaction with miRNA-487b promoting muscle regeneration and differentiation; when overexpressed, it has been shown to attenuate muscle wasting, thus being a possible therapeutic target for CA cachexia [114]. Another lncRNA that was shown to be altered in CA cachexia was cachexia-related long noncoding RNA1 (CAAlnc1), which through its interaction with the protein Hu antigen R (HuR), an essential protein for adipogenesis, led to fat loss [115].

lncMyoD is a lncRNA activated during myoblast differentiation directly by Myogenic Differentiation 1 (MyoD). When overexpressed, it has been shown to inhibit muscle differentiation and cell cycle exit, thus being associated with CA cachexia patients [116]. Recently, the lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) was found involved in expression of peroxisome proliferator activated gamma receptor (PPAR-ỿ), at the transcriptional level, associating with fat loss, and reflect a marker of worse prognosis to affected CA cachexia patients [117].

Looking for circRNAs, only one study to date has shown the expression of circRNA Hsa_circ_0010522 (ciRNA-133) in gastric CA. These circRNA was positively associated with body fat and brown fat mass. ciRNA-133 has been shown to interact as a sponge with miRNA-133 in an in vivo approach. When ciRNA-133 was overexpressed in mice, it was also shown to be increased in tumors tissue. The animals showed reduced inguinal adipose tissue mass and darkening. Therefore, ciRNA-133 worsens cancer cachexia, probably through the darkening of the fat [118].

The Figure 3 indicates the ncRNAs that have been identified to promote cardiac and cancer cachexia.

4. Non-coding RNAs and physical exercise on skeletal muscle

The health benefits of ET have been recognized for decades [119, 120]. Currently, ET is an important component in the prevention and treatment of HF and CA diseases [121, 122], as well as other chronic diseases [123]. Furthermore, being widely recommended by AHA, ESC and American Cancer Society (ACS) guidelines [124, 125]. On the other hand, no effective pharmacological therapies are available in the treatment to cachexia [20]. Indeed, ET acts directly on adaptations in skeletal muscle metabolism and morphology, inducing anabolic stimuli, which reduce muscle wasting and improve in morbidity and mortality in cachexia patient [17, 18, 24, 25, 126].

Recent studies suggest the involvement of ncRNAs, especially miRNAs, on ET-induced skeletal muscle [120, 127] and myocardium [128, 129] adaptation. In this way, potential role of ET on miRNA–mRNA networks were associated with muscle mass control, whereas ET induces skeletal muscle metabolic and myogenic pathways through miRNAs modulation [120, 130].

Although only a limited number of lncRNAs have been characterized in response to ET, the expectation of possible applications of these ncRNAs is huge. Recent study showed, through a bioinformatics analysis, the expression of lncRNAs in different ET modalities including resistance training, endurance training, high-intensity interval training, and combined ET [131]. These lncRNAs were involved with signaling pathways, such as: collagen fibril organization, extracellular matrix organization, myoblast and plasma membrane fusion, skeletal muscle contraction, synaptic transmission, PI3K/Akt/mTOR regulation, autophagy, and angiogenesis [131]. Studies validating the expression of these lncRNAs in trained human samples still needs to be evaluated. The large number of cellular functions regulated by lncRNAs and affected by ET open space for countless possibilities, becoming very promising for the future.

Even in the beginning, research involving ET and circRNAs regulation may demonstrate a possible mechanism in muscle wasting. Guo et al. [132] identified 21 circRNAs differently expressed in trained animals compared to sedentary ones. Among them, circRNA BBS9 was found reduced in aging compared to young mice and elevated expression in ET compared to sedentary aging mice. In fact, CircRNA BBS9 acts as a sponge for 10 distinct miRNAs, regulating metabolic and the PI3K/Akt/mTOR signaling pathway [132]. Besides their functions in skeletal muscle, circRNAs are promising ET biomarkers. In this way, circRNA MBOAT2 has been used in marathon athletes for cardiorespiratory assessment [133]. There are many regulatory possibilities linked to ET and ncRNAs. However, few works directly involved ncRNAs, ET, and cachexia in the literature. Below we will summarize the main findings involving this theme.

4.1 Cardiac cachexia, non-coding RNAs and physical exercise

More the one decade ago, ET was established as an important non-pharmacological strategy for HF treatment, promoting important adaptations in neurohormonal control and cardiac function [126, 134, 135]. Moreover, ET provide different biochemical, structural, and functional skeletal muscle adaptations, acting against the HF progression, and promoting capillarization, fiber type shift, oxidative metabolism improvement, and antioxidant defenses [136, 137, 138]. Important to note, skeletal muscles are highly responsive to ET stimulus [48], being able to reduce muscle wasting pathways, with E3 ligases mRNA down-regulation [77] and increasing protein synthesis (Figure 2) [48].

Many of miRNAs were altered in heart, circulation, and skeletal muscle after ET [139, 140]. Souza et al. [141] evaluated ET adaptations in rats with HF. The authors found 56 miRNAs differentially expressed in the trained group compared to sedentary. Of these, 38 miRNAs were up-regulated, and 18 miRNAs were down-regulated in trained rats. This miRNAs profile were involved with cell death, inflammation, cell metabolism, and morphology pathways [141]. Also, treadmill training may reduce the expression of miRNA-1 and -133 in the hearts of rats which are negative regulators in protein synthesis [142]. In contrast, swimming training increased expression of miRNA-21 and -144 targeting PTEN and miRNA-145 targeting tuberous sclerosis complex 2 (TSC2) [139]; whereas miRNA-124 targeting PI3K was down-regulated involved with ET-induced physiological ventricular hypertrophy. Furthermore, miRNA-17 was up-regulated in the bloodstream of exercised patients with HF, as well as rats, after ET. This increase is responsible to promote cardiomyocytes hypertrophy and proliferation, acting indirectly through PTEN and Akt signaling pathway [143]. miRNAs also regulate ET adaptation acutely, after accomplished a marathon miRNA-1, −133a, −206, and − 499 were abundantly expressed in the circulation, and 24 hours after all miRNAs, except miRNA-499, returned to baseline values. It shows that maybe these miRNAs were necessary to regulate protein synthesis in an acute way [144]. Besides, the same miRNAs were found differently expressed after 4 weeks of ET in the bloodstream, being involved in protein synthesis [145]. In conclusion, ET through miRNAs can induce molecular mechanisms related to muscle trophism acutely and chronically.

Compared to miRNAs, lncRNAs and circRNAs actions on exercise- induced muscle wasting protection remain unknown. In the heart, Lin et al. (2021) [129] evaluated the ET effects on lncRNAs expression induced by aortic constriction, showing a markedly increase in lncRNA Mhrt779 expression compared to sedentary ones. Mhrt779 expression inhibited cardiac remodeling through Hdac2/Akt/GSK-3β pathway [129]. Consequently, the lncRNAs studies are extremely important and will help to understand the ET and ncRNA in CVD, in both heart and skeletal muscle tissue.

4.2 Cancer cachexia, non-coding RNAs and physical exercise

The therapeutic strategy for CA cachexia is still open to a new treatment. However, physical fitness maintenance is widely recommended in the early disease stages [146, 147, 148]. ET attenuates CA cachexia effects through several mechanisms, such as anabolic increase, muscle homeostasis, improvement of insulin sensitivity, and control inflammation levels (Figure 2). Both aerobic ET and resistance ET were capable to reduce inflammation, through the balance of the pro and anti-inflammatory cytokines, namely TNFα, IL-6, and IL-10. In animals, this modulation, through exercise, reduced tumor volume and muscle wasting [149, 150, 151].

After resistance ET, miRNA-1 expression was down-regulated in young men and is responsible for skeletal muscle hypertrophy. In addition, miRNA-126 also induce hypertrophy by IGF-1 pathway and was down-regulated after acute exercise [131]. The PI3K/Akt/mTOR signaling pathway, once reduced either by age or disease progression, can be re-established with resistance ET [132]. ET restores the expression of 26 miRNAs differentially expressed with aging. Among these miRNAs, the family of miRNA-99 and -100, show important regulation on PI3K/Akt/mTOR signaling pathway, increasing protein synthesis, and preventing skeletal muscle atrophy [133].

Regarding muscle wasting, aerobic ET has been shown to stimulate skeletal muscle hypertrophy, reducing autophagy and the expression of E3 ubiquitin-ligases (i.e., Murf and Atrogin-1) [152, 153]. A study with the Walker-256 tumor showed that ET was able to reduce muscle wasting and to control TNF-α and IL-6 levels, oxidative damage, and E3 ubiquitin-ligases expression, acting as an anti-atrophy treatment [154]. Curiously, a study using low-intensity ET was able to inhibit the activation of the UPP and re-active mTOR pathway, suppressing phosphorylated AMPK, thus indicating that the low-intensity exercise was able to prevent CA cachexia muscle wasting [155].

Since myomiRs are tightly regulated during ET, it has been suggested that they could be used as biomarkers for monitoring cachectic patients avoiding harmful exercise, or as biomarkers for drugs that mimic exercise, such as trimetazidine [77]. In this sense, circulating miRNAs were shown to act like a biomarker for muscle loss, regeneration, therapeutic efficacy, and early detection of cachexia. We can highlight the miRNAs-130a [156], −21 [157], −203 [158], −486 [159], and myomiRs: miRNAs-1, −133a, −133b e − 206 [160, 161, 162].

5. Conclusion

Cachexia has been described as a serious health problem due to its prevalence and by affects several organs and systems. The development of cardiac and CA cachexia promotes imbalance protein system, which in turn facilitates exercise intolerance and weakness, increasingly leading to death. Therefore, understanding all the mechanisms behind this syndrome and its possible biomarkers is of great value in creating new intervention strategies.

ET has been shown to have positive results as a non-pharmacological therapy for cachexia. Its effect related to decreasing muscle degradation, inflammatory environment, fatigue, and increased survival highlights its importance within the treatment protocols for these syndromes. Current HF and CA guidelines strongly recommend regular physical exercise for stable patients to prevent and/or attenuate skeletal muscle abnormalities. Its application should incorporate the early stage of cachexia development and may be accompanied by the markers previously described. Given this, its incorporation for the treatment of cachexia only needs a focus on the syndrome. Further studies should be undertaken to explore the underlying mechanisms responsible for cardiac and CA cachexia adaptations to exercise and the regulation of ncRNAs.

Acknowledgments

The authors thank the laboratory team for their technical assistance. The researchers were supported by Sao Paulo Research Foundation (FAPESP: #2015/22814-5 and #2015/17275-8), MicroRNA Research Center (NAPmiR, University of Sao Paulo), National Council for Scientific and Technological Development (CNPq: #313479/2017-8), and Coordination for the Improvement of Higher Education Personnel (CAPES-PROEX: #88887.484856/2020-2100 and #88887.640701/2021-2100).

Conflict of interest

The authors declare no conflict of interest.