Drugs for the Treatment of Muscle Atrophy

*Linlin Chen, Hong Zhang, Mengyi Chi, Quanjun Yang and Cheng Guo*

#### **Abstract**

Muscle mass is maintained through an interplay between anabolic and catabolic pathways. The ubiquitin-proteasome system plays an important role in the proteolysis progress during skeletal muscle atrophy which can be blocked by some proteasome inhibitors. But few studies have demonstrated the ability of these inhibitors to preserve muscle mass and architecture under catabolic condition in vivo. The insulin-like growth factor-1/phosphatidylinositide 3-kinases/protein kinase B/ mammalian target of rapamycin (IGF-1/PI3K/Akt/mTOR) pathway was associated with anabolic pathways. The activation of IGF-1 causes muscle hypertrophy; however, it cannot be used as a drug target. Myostatin pathway maintains activation that can induce skeletal muscle atrophy involved with various transcriptional and genetic factors. Skeletal muscle atrophy is a debilitating consequence of multiple chronic diseases and conditions that involve starvation. It reduces treatment options and positive clinical outcomes as well as compromising quality of life and increasing morbidity and mortality. Though considerable research has been undertaken to find the drug target and the molecular mechanisms that improve skeletal muscle atrophy, no drug was approved to treat skeletal muscle atrophy. However, these years, the signaling pathways involved in muscle atrophy were clarified and some effective treatments were currently available to prevent, attenuate, or reverse muscle atrophy for experiment research.

**Keywords:** muscle atrophy, sarcopenia, cachexia, anabolic, catabolic

### **1. Introduction**

The pathophysiology of skeletal muscle atrophy is multifactorial, with cancer, sepsis, renal and cardiac failure, acquired immune deficiency syndrome (AIDS) and chronic obstructive pulmonary disease (COPD) as well as inactivity or during aging [1–3]. These factors gradually lead to muscle wasting and weakness by decreasing protein synthesis and accelerating protein degradation, which are characterized by substantial decrease in myonuclear number, muscle fiber cross-sectional area, muscle strength and protein content while increasing in fatigability and resistance to insulin [4, 5]. Muscle atrophy is recognized as an independent predictor of mortality and is associated with functional impairment and poor quality of life [6].

Studies have revealed that different types of molecular mediators/catabolic players such as pro-inflammatory cytokines i.e. tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), interleukin-1 (IL-1), interferon gamma (IFN-γ) and

TNF-like weak inducer of apoptosis (TWEAK), eicosanoids and transforming growth factor-β (TGF-β) family effectors (such as activin A and myostatin) are involved in skeletal muscle atrophy under above mentioned clinical settings [7–9]. These cytokines binding to their respective receptor results in activation of several catabolic pathways including nuclear factor-kappa B (NF-κB), Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways and small mothers against decapentaplegic homolog 2/3 (SMAD2/3). In addition to cytokines, growth factors such as insulin-like growth factor-1 (IGF-1) signal through anabolic pathway (phosphatidylinositide 3-kinases/protein kinase B/mammalian target of rapamycin; PI3K/Akt/mTOR) to mediate functional repression of the transcription factors forkhead box protein O1 (FoxO1) or FoxO3 by inhibiting their nuclear translocation and overall levels, which together inhibit the transcription of muscle atrophy genes [10].

In spite of many promising therapeutic targets for improving skeletal muscle atrophy, no treatment has been successful to date. In this chapter, we classify the potential drugs currently in laboratory/preclinical research into four categories and then discuss their mechanism of action.

### **2. Anabolic medications**

#### **2.1 Androgen/androgen receptor modulators**

Testosterone treatments increase muscle protein synthesis and fat free mass, and its effects on muscle are modulated by nutrition and exercise [11]. Several studies have shown the beneficial effects of testosterone supplementation on sarcopenia characteristics such as decreases in the muscle mass [12] and grip strength [13]. A study recently demonstrated that testosterone administration for 3 years in older men (over 60 years old) significantly improved stair-climbing power, muscle mass and power [14, 15]. Similarly, lower doses of testosterone supplementation in women with hysterectomy or chronic heart failure significantly increases lean body mass, 6-m walk time, chest press power and maximal voluntary contraction [16]. Evident showed that the effect of testosterone in improving skeletal muscle atrophy is related to the positive regulation of IGF-1 [12], wnt [17] and myostatin [18]. Although testosterone and its analogs can induce muscle growth and increase muscle strength [19], its clinical use is substantially limited by severe side effects including the increased risk of developing prostate hypertrophy, cancer, sleep apnea, masculinization, thrombosis complication and behavioral abnormalities [20, 21].

Compared with testosterone, the selective androgen receptor modulator (SARM) binds to androgen receptors with differing levels of sensitivity [22], showed androgenic effects in some tissues (such as muscle and bone), and has no effect on other organs (such as prostate or skin), thereby limiting adverse reactions such as prostate hypertrophy or androgen production. Enobosarm (GTx-024), an orally bioavailable nonsteroidal SARM, has been shown to increase lean body mass in phase I and II clinical trials of cancer cachexia patients [23, 24]. Moreover, the stimulation of reproductive organs with enobosarm seems to be less pronounced compared to testosterone administration. However, the phase III clinical trial of enobosarm failed to meet its common primary endpoint of preserving lean body mass and physical function [25]. Phase I clinical trials using another SARM non-steroidal oral preparation LGD-4033/VK5211 also showed increased muscle mass, but there was no effect on fat mass [26]. The 4-aza steroidal drug MK0773 (TFM-4AS-1) is a dual SARM and an inhibitor of 5α-reductase. Studies have shown that it can improve IGF-1 levels and muscle function in women, however,

**85**

**2.3 β-Adrenoceptor agonists**

*Drugs for the Treatment of Muscle Atrophy DOI: http://dx.doi.org/10.5772/intechopen.93503*

**2.2 Ghrelin and its receptor agonist**

the trial was terminated due to increased cardiovascular risk [27]. GSK2881078, which is assessed for its impact on muscle growth and strength, has completed its phase I trial [28] and phase II trial for the treatment of weakness caused by COPD (NCT03359473). The development of SARM drugs still requires long-term followup and/or more effective and selective SARM trials to prove the safety and efficacy

Ghrelin is a growth hormone (GH)-releasing polypeptide that binds to the GH secretagogue receptor (GHSR-1α) and stimulates appetite by activating the neuropeptide Y (NY) in the hypothalamus and helps in regulation of body weight [29, 30]. Studies have shown that ghrelin can reduce dexamethasone, fasting, denervation, cancer and cisplatin-induced muscle atrophy [31, 32]. In cachexia induced by lung adenocarcinoma, ghrelin treatment can reduce the expression of TNF-α, IL-1β, IL-6 and C-reactive protein, and inhibit skeletal muscle atrophy by restoring the expressions of the p-Akt and p-FoxO1, and reducing the expressions of p-p38 mitogen-activated protein kinase and p-NF-κB in skeletal muscle of tumor-bearing mice [33]. A three-week clinical study of ghrelin therapy in cachexia patients with nausea, COPD and chronic heart failure (CHF) showed an increase in lean body mass and muscle strength [29, 34]. Although ghrelin plays a key role in stimulating appetite, gaining body weight and preventing muscle catabolism, its clinical efficacy is limited due to its half-life (0.5 h) and route of administration (intravenous) [35]. Ghrelin agonists (such as anamorelin) have the advantage of oral activity. Compared with ghrelin (0.5 h), it has a better half-life (7–12 h) [36]. A randomized, double-blind, placebo-controlled phase I clinical study showed that anamorelin gained body weight after 6 days of treatment [37]. In two phase II anamorelin trials in cachectic patients with advanced or incurable cancer [38] and two multinational phase III trials (ROMANA 1 and 2 trials) in cachectic patients with unresectable non-small cell lung cancer (NSCLC) [39], significant gains were recorded in lean body mass and body weight over 12 weeks, but there was no improvement in physical functions and hand-grip strength. Similarly, a multicenter, open-label, single-arm study investigated the efficacy and safety of anamorelin in advanced gastrointestinal cancer patients with cancer cachexia, and this study showed a positive effect of anamorelin on lean body mass, body weight, anorexia and patients' nutritional status [40]. Furthermore, anamorelin treatment was well tolerated over 12 weeks. Finally, two meta-analyses also strongly supported the positive effect of anamorelin on lean body mass and body weight [41, 42]. Recently, a single-center study on healthy young adults showed anamorelin elicited modest increases in hunger and achieved significant increases in hunger and caloric intake [43]. The findings are consistent with multi-center findings in cachectic cancer patients and

expand the evidence supporting anamorelin as a potential intervention.

Muscle growth can also be stimulated by activation of G-protein coupled β2-adrenoreceptor (β2-AR), which causes protein kinase A activation [44] and thereby stimulating PI3K/Akt/mTOR signaling [45]. Formoterol is a β2-AR agonist, the administration of formoterol significantly increased the levels of follistatin and decreased the levels of myostatin and its receptors (activin receptor IIB, ActRIIB) in tumor-bearing rats, thereby regulating muscle mass loss [46, 47]. In addition to skeletal muscle, formoterol also shows a strong protective effect on the

of SARM in improving physical function and health outcomes.

#### *Drugs for the Treatment of Muscle Atrophy DOI: http://dx.doi.org/10.5772/intechopen.93503*

*Background and Management of Muscular Atrophy*

then discuss their mechanism of action.

**2.1 Androgen/androgen receptor modulators**

**2. Anabolic medications**

TNF-like weak inducer of apoptosis (TWEAK), eicosanoids and transforming growth factor-β (TGF-β) family effectors (such as activin A and myostatin) are involved in skeletal muscle atrophy under above mentioned clinical settings [7–9]. These cytokines binding to their respective receptor results in activation of several catabolic pathways including nuclear factor-kappa B (NF-κB), Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways and small mothers against decapentaplegic homolog 2/3 (SMAD2/3). In addition to cytokines, growth factors such as insulin-like growth factor-1 (IGF-1) signal through anabolic pathway (phosphatidylinositide 3-kinases/protein kinase B/mammalian target of rapamycin; PI3K/Akt/mTOR) to mediate functional repression of the transcription factors forkhead box protein O1 (FoxO1) or FoxO3 by inhibiting their nuclear translocation and overall levels, which together inhibit the transcription of muscle atrophy genes [10]. In spite of many promising therapeutic targets for improving skeletal muscle atrophy, no treatment has been successful to date. In this chapter, we classify the potential drugs currently in laboratory/preclinical research into four categories and

Testosterone treatments increase muscle protein synthesis and fat free mass, and its effects on muscle are modulated by nutrition and exercise [11]. Several studies have shown the beneficial effects of testosterone supplementation on sarcopenia characteristics such as decreases in the muscle mass [12] and grip strength [13]. A study recently demonstrated that testosterone administration for 3 years in older men (over 60 years old) significantly improved stair-climbing power, muscle mass and power [14, 15]. Similarly, lower doses of testosterone supplementation in women with hysterectomy or chronic heart failure significantly increases lean body mass, 6-m walk time, chest press power and maximal voluntary contraction [16]. Evident showed that the effect of testosterone in improving skeletal muscle atrophy is related to the positive regulation of IGF-1 [12], wnt [17] and myostatin [18]. Although testosterone and its analogs can induce muscle growth and increase muscle strength [19], its clinical use is substantially limited by severe side effects including the increased risk of developing prostate hypertrophy, cancer, sleep apnea, masculinization, thrombosis complication and behavioral abnormalities [20, 21]. Compared with testosterone, the selective androgen receptor modulator (SARM) binds to androgen receptors with differing levels of sensitivity [22], showed androgenic effects in some tissues (such as muscle and bone), and has no effect on other organs (such as prostate or skin), thereby limiting adverse reactions such as prostate hypertrophy or androgen production. Enobosarm (GTx-024), an orally bioavailable nonsteroidal SARM, has been shown to increase lean body mass in phase I and II clinical trials of cancer cachexia patients [23, 24]. Moreover, the stimulation of reproductive organs with enobosarm seems to be less pronounced compared to testosterone administration. However, the phase III clinical trial of enobosarm failed to meet its common primary endpoint of preserving lean body mass and physical function [25]. Phase I clinical trials using another SARM non-steroidal oral preparation LGD-4033/VK5211 also showed increased muscle mass, but there was no effect on fat mass [26]. The 4-aza steroidal drug MK0773 (TFM-4AS-1) is a dual SARM and an inhibitor of 5α-reductase. Studies have shown that it can improve IGF-1 levels and muscle function in women, however,

**84**

the trial was terminated due to increased cardiovascular risk [27]. GSK2881078, which is assessed for its impact on muscle growth and strength, has completed its phase I trial [28] and phase II trial for the treatment of weakness caused by COPD (NCT03359473). The development of SARM drugs still requires long-term followup and/or more effective and selective SARM trials to prove the safety and efficacy of SARM in improving physical function and health outcomes.

### **2.2 Ghrelin and its receptor agonist**

Ghrelin is a growth hormone (GH)-releasing polypeptide that binds to the GH secretagogue receptor (GHSR-1α) and stimulates appetite by activating the neuropeptide Y (NY) in the hypothalamus and helps in regulation of body weight [29, 30]. Studies have shown that ghrelin can reduce dexamethasone, fasting, denervation, cancer and cisplatin-induced muscle atrophy [31, 32]. In cachexia induced by lung adenocarcinoma, ghrelin treatment can reduce the expression of TNF-α, IL-1β, IL-6 and C-reactive protein, and inhibit skeletal muscle atrophy by restoring the expressions of the p-Akt and p-FoxO1, and reducing the expressions of p-p38 mitogen-activated protein kinase and p-NF-κB in skeletal muscle of tumor-bearing mice [33]. A three-week clinical study of ghrelin therapy in cachexia patients with nausea, COPD and chronic heart failure (CHF) showed an increase in lean body mass and muscle strength [29, 34]. Although ghrelin plays a key role in stimulating appetite, gaining body weight and preventing muscle catabolism, its clinical efficacy is limited due to its half-life (0.5 h) and route of administration (intravenous) [35].

Ghrelin agonists (such as anamorelin) have the advantage of oral activity. Compared with ghrelin (0.5 h), it has a better half-life (7–12 h) [36]. A randomized, double-blind, placebo-controlled phase I clinical study showed that anamorelin gained body weight after 6 days of treatment [37]. In two phase II anamorelin trials in cachectic patients with advanced or incurable cancer [38] and two multinational phase III trials (ROMANA 1 and 2 trials) in cachectic patients with unresectable non-small cell lung cancer (NSCLC) [39], significant gains were recorded in lean body mass and body weight over 12 weeks, but there was no improvement in physical functions and hand-grip strength. Similarly, a multicenter, open-label, single-arm study investigated the efficacy and safety of anamorelin in advanced gastrointestinal cancer patients with cancer cachexia, and this study showed a positive effect of anamorelin on lean body mass, body weight, anorexia and patients' nutritional status [40]. Furthermore, anamorelin treatment was well tolerated over 12 weeks. Finally, two meta-analyses also strongly supported the positive effect of anamorelin on lean body mass and body weight [41, 42]. Recently, a single-center study on healthy young adults showed anamorelin elicited modest increases in hunger and achieved significant increases in hunger and caloric intake [43]. The findings are consistent with multi-center findings in cachectic cancer patients and expand the evidence supporting anamorelin as a potential intervention.

#### **2.3 β-Adrenoceptor agonists**

Muscle growth can also be stimulated by activation of G-protein coupled β2-adrenoreceptor (β2-AR), which causes protein kinase A activation [44] and thereby stimulating PI3K/Akt/mTOR signaling [45]. Formoterol is a β2-AR agonist, the administration of formoterol significantly increased the levels of follistatin and decreased the levels of myostatin and its receptors (activin receptor IIB, ActRIIB) in tumor-bearing rats, thereby regulating muscle mass loss [46, 47]. In addition to skeletal muscle, formoterol also shows a strong protective effect on the

heart muscle [48]. Clinical studies have also shown that formoterol treatment can increase the content of PGC-1α and mtDNA in skeletal muscle of COPD patients to enhance the oxidation process of skeletal muscle and improve exercise ability [49]. Clenbuterol is another β2-AR agonist and can improve skeletal muscle atrophy in a variety of muscle atrophy models dominated by denervation [50], immobilization [51] and spinal cord injury [52]. However, due to concerns about potential cardiovascular side effects [44, 53], such as cardiac arrhythmia, there has been little interest in the clinical applications of β2-AR agonists for muscle atrophy treatment. Among them, espindolol may be a potentially attractive compound. It is a β1 receptor antagonist, a partial β2 receptor agonist and also has 5-HT1a receptor activities. In old rats, espindolol has been shown to significantly increase muscle mass, while reducing fat mass without negatively affecting heart function [54]. In addition, it has also shown very promising results in phase IIa cancer cachexia studies leading to increased muscle mass and grip strength [55, 56].
