Myostatin and muscle atrophy during chronic kidney disease

Abstract

Chronic kidney disease (CKD) patients often exhibit a low muscle mass and strength, leading to physical impairment and an increased mortality. Two major signalling pathways control protein synthesis, the insulin-like growth factor-1/Akt (IGF-1/Akt) pathway, acting as a positive regulator, and the myostatin (Mstn) pathway, acting as a negative regulator. Mstn, also known as the growth development factor-8 (GDF-8), is a member of the transforming growth factor-β superfamily, which is secreted by mature muscle cells. Mstn inhibits satellite muscle cell proliferation and differentiation and induces a proteolytic phenotype of muscle cells by activating the ubiquitin–proteasome system. Recent advances have been made in the comprehension of the Mstn pathway disturbance and its role in muscle wasting during CKD. Most studies report higher Mstn concentrations in CKD and dialysis patients than in healthy subjects. Several factors increase Mstn production in uraemic conditions: low physical activity, chronic or acute inflammation and oxidative stress, uraemic toxins, angiotensin II, metabolic acidosis and glucocorticoids. Mstn seems to be only scarcely removed during haemodialysis or peritoneal dialysis, maybe because of its large molecule size in plasma where it is linked to its prodomain. In dialysis patients, Mstn has been proposed as a biomarker of muscle mass, muscle strength or physical performances, but more studies are needed in this field. This review outlines the interconnection between Mstn activation, muscle dysfunction and CKD. We discuss mechanisms of action and efficacy of pharmacological Mstn pathway inhibition that represents a promising treatment approach of striated muscle dysfunction. Many approaches and molecules are in development but until now, no study has proved a benefit in CKD.

chronic kidney disease, myostatin, sarcopenia, wasting

INTRODUCTION

The association of skeletal muscle atrophy and impaired muscle function, named sarcopenia, is associated with lower health-related quality of life, and greater disability and mortality risk in chronic kidney disease (CKD) patients [1, 2]. Its prevalence is estimated to be between 12% and 29% and it represents an important medico-economic burden [3, 4].

In healthy adults, a constant muscle mass is maintained through the balance of the insulin-like growth factor-1/Akt (IGF-1/Akt) pathway inducing protein synthesis and recruitment of muscle satellite cells on one hand, and the myostatin (Mstn) pathway inducing protein breakdown by activation of the ubiquitin–proteasome pathway and caspase3 as well as inhibiting satellite cell recruitment on the other hand [5–7]. These two pathways are highly regulated and interact with one another. Muscle loss comes from a disequilibrium between these two systems [8].

A better understanding of this system in CKD-associated muscle dysfunction is crucial. Recent advances in the role of Mstn as well as development of potential therapeutic molecules give rise to great hope for future treatments.

MOLECULAR PATHWAYS OF MUSCLE MASS REGULATION

The main muscle growth pathway is the IGF-1/Akt (Figure 1). Activation of this signalling pathway is initiated by the interaction of IGF-1—a hepatic synthetized growth factor after stimulation of the growth hormone (GH)—with its receptor (IGF-1R) at muscle cell surface [9]. The binding of IGF-1 to its receptor leads to Akt phosphorylation into p-Akt. Akt, also called protein kinase B, regulates more than 2000 genes of mammalian target of rapamycin complex 1 (mTORC1). mTORC1 and its downstream effectors are an important protein synthesis pathway. In muscle cells, it can be activated by p-Akt as well as by other mechanical or hormonal stimuli in order to activate muscle growth.

FIGURE 1

Activation and signalling pathway explaining muscle wasting and cachexia in patients with CKD. CKD is associated with an increase in circulating inflammatory cytokines, uraemic toxins and oxidative stress combined with reduction of physical activity, which sets the stage for the activation of Mstn. Mstn binds to ActRIIB/IIB on muscle cell membrane. Subsequent phosphorylation of Smad2/3 leads to its binding with Smad4 and translocation of the complex to the nucleus, where it blocks the transcription of genes responsible for the myogenesis. Mstn also reduces Akt activity and decreases FoxO phosphorylation. Dephosphorylated FoxO enters the nucleus to activate transcription of MuRF1 and Atrogin-1, which cause muscle protein ubiquitination and degradation by the proteasome and autophagy. Mstn also active p38/caspase pathways that are involved in apoptosis. Mstn also suppresses the mTORC1 pathway and protein synthesis. This leads to muscle wasting and cachexia. ActRIIA, activin receptor type IIA; ActRIIB, activin receptor type IIB; ALK, anaplastic lymphoma receptor tyrosine kinase; eIF4G, eukaryotic translation initiation factor 4 G; IL, interleukin; JAK, Janus kinase; mTORC1, mammalian target of rapamycin complex 1; P, phosphorylation; SMAD, Sma- and Mad-related protein; TNF-α, tumor necrosis factor alpha.

Besides its central role in proteo-synthesis activation, p-Akt also suppresses the proteolytic cell activity by inactivating and maintaining in the cytoplasm the forkhead box O (FoxO) transcription factors resulting in the ubiquitin–proteasome system (UPS) as well as the autophagy–lysosomal proteolytic pathways activation [10].

On the other side, the main negative regulator of muscle cells is the Mstn pathway, which activates the UPS in mature muscle cells and inhibits muscle satellite cell recruitment (Figure 1). Mstn, or growth development factor-8 (GDF-8), is a member of the transforming growth factor-β (TGF-β) superfamily. It is mainly secreted by mature muscle cells, and to a lesser extent in smooth muscle cells, heart, adipocytes, mammary glands and haematopoietic stem cells [11]. Mstn is produced by muscle cells as a pre-pro-myostatin, then secreted in the intercellular space and blood as pro-myostatin. After a two-step cleavage from its prodomain, called latency-associated protein (LAP) in its active dimeric form, Mstn acts as a potent autocrine, paracrine and endocrine negative regulator of muscle growth [11].

At muscle cell surface, Mstn binds to its receptor activin type II B receptor (ActRIIB) leading to phosphorylation and activation of transcription factors Smad2 and Smad3 [12] (Figure 1). The Smads are then imported into the nucleus where they modulate transcription of target genes. They increase the transcription of Atrogin-1 (or muscle atrophy F-box, MAFbx) and muscle RING finger 1 (Murf-1), two E3 ubiquitin ligases, stimulating protein breakdown via the UPS [13]. Smad2 and -3 also inhibit Akt phosphorylation and the Janus kinase/Stat pathway [12]. Other members of the TGF-β superfamily such as Activin A or GDF-11 are also able to bind to ActRIIB and induce the same cell signal. Mstn is not the only negative regulator of muscle mass during CKD. Metabolic acidosis or endogenous glucocorticoids inhibit phosphoinositide 3-kinase activation and therefore Akt phosphorylation [14, 15]. Inflammation as well, and notably interleukin (IL)-6, inhibits muscle protein synthesis via Stat3 activation and possibly increases Mstn transcription [16, 17].

Satellite muscle cells are partially differentiated quiescent stem cells living at the periphery of muscle fibres. When muscle fibres are wounded, satellite cells activated by growth factors proliferate, differentiate and fuse, leading to new muscle fibers. Alteration of the IGF-1/Akt pathway as well as binding of Mstn to satellite cells inhibit their proliferation and differentiation [18].

ANATOMIC AND METABOLIC EFFECTS OF MYOSTATIN

The numerous natural or experimental Mstn knock-out animal models of cattle, mice or dog exert an impressive muscle mass increase and confirm the relationship between Mstn and muscle growth inhibition [19]. Interestingly, muscle strength and physical performance of these models are proportionally less increased than their muscle mass, and are associated with earlier muscle fatigue. This fatigue is linked to a shift of an aerobic to anaerobic energetic metabolism and consequently lactic acid production during exercise. In human, an observation of a loss-of-function mutation in the Mstn gene has been reported in a 4-year-old boy who showed a significant muscle hypertrophy since birth [20]. Interestingly, his heterozygous mother also had a high muscle mass, but not as high as his son. Mstn polymorphisms have been associated with muscle strength in human [21].

Opposite this, administration of Mstn or Activin A in mice induces a 30% muscle mass reduction. Mstn is increased in various animal models of muscle dystrophy, cachexia and immobilization. In human, Mstn expression increases with age. In sarcopenic elderly, Mstn is positively correlated with muscle atrophy. This correlation is also found in young individuals after immobilization as well as in several pathologic states: corticosteroid therapy, cancer, acquired immunodeficiency syndrome, heart failure and chronic obstructive pulmonary disease [22].

Besides its negative regulator of muscle growth, Mstn also interferes with several metabolic pathways including lipid storage, insulin sensitivity and thermogenic regulation. Mstn is upregulated in obese patients and correlates with insulin resistance [23]. Bariatric surgery lowers Mstn expression and improves insulin sensitivity. These results suggest that the association of sarcopenia, obesity and type II diabetes could constitute a target for Mstn inhibitors.

Insulin sensitivity is not only due to an increase in muscle mass. The phosphorylation of Akt increases the muscle fibre expression of glucose transporters GLUT-1 and GLUT-4, and glycogen synthesis, improving glucose muscle uptake [24]. These observations are supplemental arguments to developing Mstn inhibitors to increase insulin sensitivity.

MYOSTATIN DURING CKD

Low physical activity, chronic or acute inflammation and oxidative stress, accumulation of uraemic toxins, angiotensin II, metabolic acidosis and glucocorticoids observed in CKD patients are all factors that may contribute to increase in Mstn production [8, 25] (Figure 1); although, limited data are available on the role of Mstn upregulation in the alterations in skeletal muscle mass in the field of CKD. In human, most data are observational and only few animal models have been studied.

In a rat subtotal nephrectomy CKD model, muscle Mstn mRNA was increased compared with pair-fed rats and, after 2–7 days of exercise returned to normal values. At the same time, muscle mass and IGF-1 mRNA were increased [26]. In a 5/6 nephrectomy mice model, CKD mice display higher IL-6, Mstn and Atrogin-1 mRNA in gastrocnemius muscle and lower Akt phosphorylation [27]. The same team reported in vitro in myotubes that, indoxyl sulfate(IS), an indolic uraemic toxin, was involved in the expression of IL-6, Mstn and Atrogin-1. They confirmed these results in vivo and chronic treatment of IS in half-nephrectomized mice was able to increase the same genes in muscle, but curiously they did not find any change in Akt phosphorylation [28]. These data suggest that IS could upregulate Mstn secretion and be a major player of muscle dysfunction during CKD, but this link must be confirmed in CKD patients.

In human, a vastus lateralis transcriptome study performed in five haemodialysis (HD) patients before their dialysis session did not report any change in Mstn or Atrogene mRNA expression compared with healthy subjects [29]. Another study performed in 51 younger (mean age 42 years old) HD patients did not show any increase in Mstn mRNA in vastus lateralis compared with healthy subjects [30]. Nevertheless, in rectus abdominis muscle biopsies performed at the time of peritoneal catheter insertion in 22 CKD Stage 5 patients, Verzola et al. reported that Mstn mRNA was 10 times higher than in 22 paired healthy subjects and Mstn protein concentration 4 times higher [31]. Enzyme-linked immunosorbent assay (ELISA) and western blot can be performed to measure tissue Mstn concentrations, but as for plasma Mstn dosing, the specificity of available antibodies for each of the Mstn forms (active Mstn, monomer or dimer form, pro-myostatin) is not so clear. Overall, muscle tissue Mstn concentration seems to be increased during CKD, at least in some patients, but more studies are needed to better describe how Mstn acts as a local signal to promote atrophy.

Inflammation could be the trigger of Mstn overexpression during CKD. Indeed, Verzola et al. observed that CKD patients had a higher IL-6 mRNA in muscle and that Mstn gene overexpression was correlated with inflammation parameters in this population [31]. In good concordance, Zhang et al. reported high levels of pro-inflammatory cytokines including IL-6 in muscle biopsies of 18 CKD patients, which activate transcription factors including Stat3. Stat3 expression is increased in animals and human during CKD and upregulate Mstn gene expression. Interestingly, Stat3 knockout mice in muscle exert no inflammation and no muscle atrophy after CKD induction [16]. Physical activity could also be a clue: a study in HD reported a 50% decrease in Mstn mRNA in vastus lateralis muscle after only 9 weeks of endurance exercise training [32].

In human, the few studies having reported plasma concentrations of Mstn during CKD are described in Table 1. Concentrations and results are highly influenced by the dosing technique, age and gender. Nevertheless, most studies report higher Mstn concentrations in CKD, HD and peritoneal dialysis (PD) patients than in healthy subjects.

Table 1

Studies of myostatin plasma concentrations in CKD and dialysis patients

Population	Assay techniques	Mstn concentration in population	Results	Study
Non-dialysis CKD
93 CKD patients	R&D Systems, Abingdon, UK	3.34 ng/mL	Negative correlation with eGFR (β = −0.31, P < 0.01) and ClCr (β = −0.35, P < 0.01) Higher than in healthy subjects	Yano et al. [33]
78 CKD Stage 1 diabetic nephropathy patients	Usc life Science & Technology Co., Ltd, Wuhan, China	8.1 ± 1.3 ng/mL	Higher than in healthy subjects (5.3 ± 0.9 ng/mL; P < 0.001)	Yilmaz et al. [34]
Group A: 26 ADPKD CKD patients (eGFR 45–70 mL/min/1.73 m2) Group B: 26 ADPKD without CKD patients	R&D Systems, Abingdon, UK	4.62 ± 0.59 ng/mL in group A 3.06 ± 0.35 ng/mL in group B (P < 0.001 compared with group A)	Higher in group A and B than in healthy subjects (2.18 ± 0.45 ng/mL; P < 0.001 compared with each group)	Raptis et al. [35]
HD
10 HD patients	R&D Systems, Abingdon, UK	3376 ± 1723 pg/mL	No difference compared with healthy subjects	Cavalier et al. [36]
10 HD patients	R&D Systems, Minneapolis, MN, USA	6 ± 3.4 ng/mL	Higher than in healthy subjects (3.1 ± 0.6 ng/mL) although not significant (P = 0.07)	Esposito et al. [37]
140 HD patients	Cloud-Clone Corp., USA	40.18 ± 8.36 ng/mL	Higher than in healthy subjects (2.5 ± 2.4 ng/mL; P < 0.001)	Koyun et al. [38]
37 HD patients 34 PD patients	R&D Systems, Minneapolis, MN, USA	5.3 ± 2.6 ng/mL	No control group	Lee et al. [39]
60 HD patients	Homemade ELISA	25.7 ± 12.8 µg/mL	No difference compared with healthy subjects	Han et al. [40]
204 HD patients	R&D Systems, Minneapolis, MN, USA	2573 (1662–3703) pg/mL	No control group	Delanaye et al. [41]
69 PD patients	R&D Systems, Minneapolis, MN, USA	7.59 ± 3.37 ng/mL	No control group No difference according to residual renal function (r = 0.079, P = 0.510)	Yamada et al. [42]

eGFR, estimated glomerular filtration rate; ClCr, creatinine clearance; ADPKD, autosomal dominant polycystic kidney disease.

Active Mstn is a small 25 kDa dimer and could theoretically be removed during HD or haemodiafiltration (HDF). However, in plasma, active Mstn is mainly linked to its prodomain, forming a 43 kDa protein or 86 kDa protein when dimerized. Thus, dialysis modality could only partly influence Mstn concentration. In a study comparing 60 HD patients, those who were dialysed with high-flux membrane had higher grip strength and lower Mstn concentrations. Mstn concentrations decreased to 36% during the dialysis session in patients with a high-flux membrane but increased to 25% in those with low-flux membranes; however, the dosing of the assay was not described [40]. Delanaye et al. report a 12% decrease in Mstn concentrations during a 4 h high-flux dialyser HD session, but did not find any effect of HDF on conventional HD [41]. Another study in 32 HD patients reports similar removal rates between the two techniques [43]. However, in a crossover study comparing Mstn concentrations after 3 months HD and 3 months HDF, Mstn was significantly lower after the HDF period [37]. Mstn concentrations seem not to be influenced by peritoneal clearance [42].

In HD patients, the correlation between Mstn concentrations and muscle function and mass is contradictory [38–42, 44] (Table 2). Mstn is positively associated with muscle mass or strength in most studies. Since Mstn is produced by muscle cells, its concentration might only be a surrogate marker of muscle mass [41]. Supporting this hypothesis, Zhou et al. report an increase in serum myostatin in CKD patients after 12 months of strength exercise [44]. More recently, an observational study reported an independent correlation between Mstn concentrations and vascular calcifications in PD and HD patients [39].

Table 2

Studies of myostatin plasma concentrations in CKD and dialysis patients and association with muscle parameters

Population	Results	Study
140 HD patients	Mstn not correlated with ASMI (r = 0.042, P = 0.624)	Koyun et al. [38]
20 PD or HD patients	Mstn positively correlated with ASMI (r = 0.516, P = 0.020)	Lee et al.[39]
60 HD patients	Mstn inversely correlated with handgrip strength (r = −0.36, P < 0.01)	Han et al. [40]
69 PD patients	Mstn positively correlated with LBM (r = 0.57, P < 0.001)	Yamada et al. [42]
204 HD patients	Mstn positively correlated with handgrip strength (r = 0.37, 95% CI 0.25–0.48, P < 0.0001) Mstn positively correlated with muscle mass index (r = 0.30, 95% CI 0.07–0.50, P = 0.01)	Delanaye et al. [41]
151 CKD patients	Mstn is positively correlated with handgrip strength (P < 0.001), isometric quadriceps strength (P < 0.001) Mstn is positively correlated with arm lean mass (P < 0.001), leg lean mass (P < 0.001) and trunk lean mass (P = 0.001)	Zhou et al. [44]

ASMI, appendicular skeletal muscle mass index; CI, confidence interval; LBM, lean body mass.

Overall, several issues may lead to an increase in Mstn in CKD: an increased production under physical inactivity, inflammation, and maybe uraemic toxin triggers and Mstn removal decreases. However, data are lacking on the potential role of kidney on Mstn removal. All these phenomena participate in sarcopenia in CKD [12].

INHIBITION OF THE MYOSTATIN PATHWAY

Mstn pathway inhibition represents a promising therapeutic approach in situations associated with striated muscle dysfunction such as myopathy, cancer or sarcopenia associated with chronic diseases including CKD. Many strategies are proposed to inhibit the Mstn pathway. The majority of them act extracellularly to block Mstn engaging with the ActRIIB receptor complex, either by binding directly to Mstn itself or by binding to components of this receptor complex (Figure 2).

FIGURE 2

Inhibitors of myostatin used in experimental and clinical trials. ActRII, activin receptor type II; ALK, anaplastic lymphoma receptor tyrosine kinase.

Follistatin, the main natural Mstn inhibitor, not only inhibits Mstn’s ligation to its receptor, but is also able to link to other TGF-β family members including Activin A that also regulate negatively muscle growth. As a result, in animal models, follistatin increases satellite cell recruitment, muscle strength and muscle mass [45]. Of note, follistatin plasma concentration is positively correlated with age and inflammatory markers in CKD, but is not associated with renal function [46]. Other natural proteins are involved in Mstn regulation: follistatin-related gene and follistatin-like 3, which inhibit Activin A; growth and differentiation factor-associated serum protein-1 (GASP-1), which shares structural similarities with follistatin; and the soluble ActRIIB, which binds to Activin A or Mstn in the plasma and inhibits their activity on target cells. Therefore, in healthy mice, treatments with these natural inhibitors (follistatin, GASP-1) confirm an increase in muscle mass [47, 48].

Most exogenous Mstn pathway inhibitors are Mstn, Activin A or ActRIIB neutralizing antibodies. In wild-type mice, treatment with monoclonal antibody directed against Mstn [49] or using a mutant inactive form of the Mstn propeptide [50] is capable of increasing muscle mass by almost 25%. As natural molecules, most of these inhibitors reduce protein catabolism, increase Akt phosphorylation and reduce concentrations of inflammatory cytokines including IL-6. They mainly increase protein synthesis in myofibrils, and to a lesser extent promote satellite cell recruitment and myogenesis. Recently, a novel approach with an antibody (SRK-015) targeting the pro-myostatin and blocking the release of the active Mstn has also been developed [11].

In different experiment models of skeletal muscle disease like amyotrophic lateral sclerosis or muscular dystrophy, efficay of first developed anti-Mstn antibodies [49] is contradictory to survival improvements and muscle mass depending on the strategy to inhibit Mstn. Therefore, more specific anti-Mstn antibodies have been developed [11]. Special care has been taken so that these treatments do not activate other TGF-β pathways that could lead to undesirable effects, and previously led a therapeutic trial to premature stop [51]. Anti-Mstn antibody (REGN1033) prevented the loss of muscle mass induced by immobilization, glucocorticoid treatment or with age in mice [52]. Other anti-Mstn antibodies, PF-354 or ATA 842 [53], prevented muscle loss due to ageing and cancer cachexia. In a model of stroke, a better recovery of skeletal muscle mass was observed in mice treated with the anti-Mstn protein PINTA745 [54]. Finally, ActRIIB antagonist or anti-ActRIIB antibody (bimagrumab/BYM338) has positive effects on muscle mass in mouse models of cancer cachexia or glucocorticoid-induced atrophy [55]. Encouraging results are observed with double inhibition of Mstn with Mstn-targeting siRNA and ActRIIB antagonist [56]. Follistatin confirms its therapeutic potential in models of skeletal muscle atrophy but GASP1/2 has not yet been tested in models of muscle wasting.

In CKD, preliminary study by Zhang et al. demonstrated that injections of an anti-Mstn peptibody into uraemic mice reversed loss of body weight and increased muscle mass by 10% [17]. Counteracting Mstn was able to decrease protein degradation rate and inflammation, and prevent fibrosis in skeletal muscles and suppress the proliferation of fibro/adipogenic progenitor cells. An inhibitor of Stat3 (C188-9) prevented activation of Mstn and CKD-induced muscle wasting [16]. Until now, no other pharmacology strategy in CKD has been tested.

Several Phase 1 or Phase 2 studies have been performed or are currently ongoing with different Mstn inhibitors, in the field of geriatrics, muscle dystrophy or oncology. For example, landogrozumab (LY2495655) increases lean mass and might improve functional measures of muscle power in the elderly [57]. This antibody is actually being tested in patients with advanced cancer (NCT01524224). Stamulumab (MYO-029) was tested in Duchenne muscular dystrophy, but the results were not as good as expected and the trial was stopped. In the same disease, antibody domagrozumab (PF-06252616) (NCT02907619) and an anti-Mstn Adnectin fusion protein talditercept alpha (BMS-986089/RG6206) (NCT03039686) have actually been studied. A Phase 2 study (NCT01963598) on safety and efficacy of antibody trevogrumab (REGN1033) has been completed in sarcopenic subjects, although the results are not yet available. Antibodies anti-ActRIIB (bimagrumab/BYM-338) increased muscle mass and strength in older adults with sarcopenia and improved mobility in those with slow walking speed [58]. Also, ACE031 (soluble activin receptor type IIB) showed an increase in lean body mass and attenuation of declines in 6-min walk distance in Duchenne muscular dystrophy [51]. Different activin inhibitors are used in ongoing trials like STM 434 in cancer cachexia (NCT02262455). AMG745/PINTA745, a peptibody against Mstn has been tested in age-associated muscle loss (NCT00975104) and in patients with inclusion myositis (NCT01925209).

In CKD patients, only one Phase 2 randomized, placebo-controlled trial has been performed with AMG745/PINTA745. The encouraging improvement of muscle strength and mass in mice led to a 12-week pilot trial in 51 HD patients with protein-energy wasting syndrome (NCT01958970). Unfortunately, the results of the trial have not been published and development of drugs was stopped because the trial did not meet its primary endpoint, defined as the percent change from baseline in lean body mass as measured by dual energy X-ray absorptiometry at Week 12 following weekly treatment. PINTA 745 also did not improve physical function, measures of glycaemic control and markers of inflammation.

Safety questions were raised about the long-term effect of exposure to Mstn inhibition. ACE-031, a soluble ActRIIB, induced bleeding and telangiectasias and led to a premature stop of a clinical trial [51]. Also, Mstn is expressed in heart, which raises the possibility of cardiomyopathy with sustained Mstn inhibition [59]. On the other hand, the increase in insulin sensitivity combined with an advantageous lipid profile and a possible anti-fibrotic effect on cardiac tissue would come as a welcome side effect [60].

Improvement of factors favouring Mstn overexpression is also an important clue: reducing metabolic acidosis, inflammation, angiotensin II, malnutrition or lack of exercise is a first-line therapy. Physical exercise has been shown to improve muscle mass and function, but to reduce Mstn production in uraemic mice. In HD patients, a 21-week training course combining endurance and resistance exercises led to an increase in IGF-1 mRNA in vastus lateralis muscle biopsies, and a reduction in Mstn mRNA. At the same time, muscle mass was increased and fat mass decreased [61]. Follistatin production is also increased during physical exercise. More studies are needed to better understand the effect of physical exercise on Mstn production and activity during CKD.

CONCLUSION

Muscle mass and function impairment during CKD is a major morbimortality contributor, especially in elderly who associate age sarcopenia with uraemic sarcopenia. Mstn, which is a major stakeholder of muscle protein catabolism in muscle cells and inhibits muscle repair and satellite cell recruitment, is increased in plasma of CKD patients for several reasons, including decreased Mstn clearance. This accumulation participates in uraemic muscle dysfunction, although its pathophysiological comprehension requires further studies. Mstn inhibitors could constitute a promising therapeutic approach in this field, in addition to physical activity and conventional CKD treatments. Much remains to be discovered regarding the biology of the Mstn pathway to inform the development of specific inhibitors and its efficiency in uraemic conditions.

CONFLICT OF INTEREST STATEMENT

The authors have no competing interests to declare. The results presented in this paper have not been published previously in whole or part.