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Muscular myostatin gene expression and plasma concentrations are decreased in critically ill patients



The objective was to investigate the role of gene expression and plasma levels of the muscular protein myostatin in intensive care unit-acquired weakness (ICUAW). This was performed to evaluate a potential clinical and/or pathophysiological rationale of therapeutic myostatin inhibition.


A retrospective analysis from pooled data of two prospective studies to assess the dynamics of myostatin plasma concentrations (day 4, 8 and 14) and myostatin gene (MSTN) expression levels in skeletal muscle (day 15) was performed. Associations of myostatin to clinical and electrophysiological outcomes, muscular metabolism and muscular atrophy pathways were investigated.


MSTN gene expression (median [IQR] fold change: 1.00 [0.68–1.54] vs. 0.26 [0.11–0.80]; p = 0.004) and myostatin plasma concentrations were significantly reduced in all critically ill patients when compared to healthy controls. In critically ill patients, myostatin plasma concentrations increased over time (median [IQR] fold change: day 4: 0.13 [0.08/0.21] vs. day 8: 0.23 [0.10/0.43] vs. day 14: 0.40 [0.26/0.61]; p < 0.001). Patients with ICUAW versus without ICUAW showed significantly lower MSTN gene expression levels (median [IQR] fold change: 0.17 [0.10/0.33] and 0.51 [0.20/0.86]; p = 0.047). Myostatin levels were directly correlated with muscle strength (correlation coefficient 0.339; p = 0.020) and insulin sensitivity index (correlation coefficient 0.357; p = 0.015). No association was observed between myostatin plasma concentrations as well as MSTN expression levels and levels of mobilization, electrophysiological variables, or markers of atrophy pathways.


Muscular gene expression and systemic protein levels of myostatin are downregulated during critical illness. The previously proposed therapeutic inhibition of myostatin does therefore not seem to have a pathophysiological rationale to improve muscle quality in critically ill patients.

Trial registration: ISRCTN77569430—13th of February 2008 and ISRCTN19392591 17th of February 2011.

Graphical abstract


Intensive care unit-acquired weakness (ICUAW) is defined as a clinically relevant muscular weakness with critical illness itself as the most plausible etiology developing in at least 40% of ICU patients [1,2,3]. ICUAW can be classified in critical illness myopathy (CIM) and/or critical illness polyneuropathy (CIP) and has detrimental effects on weaning from mechanical ventilation, length of hospital stay and ICU mortality as well as long-term outcomes (e.g., physical function, health-related quality of life and survival) [3,4,5]. Severe muscle atrophy with a muscle mass decrease of 4% per day accompanies the described ICUAW [6,7,8]. Even though a latter increase in muscle mass (6-month post-ICU discharge) has been described, atrophy is still evident in most patients [9]. The ubiquitin–proteasome system as a key pathway of muscle protein degradation is activated early during critical illness. Simultaneously, a reduction in muscle protein synthesis measured via myostatin heavy chain expression can be observed [3, 6], whereas incorporation of labeled amino acid does not show a decrease [10]. Besides, muscle atrophy is insulin resistance also commonly present during critical illness and especially pronounced in patients with neuromuscular dysfunction [11]. It has been shown that overcoming insulin resistance via intensive insulin therapy has a protective effect for the neuromuscular function in critically ill patients [12, 13]. While these mechanisms contribute largely to the clinical weakness, the definitive pathophysiology of ICUAW remains under investigation.

Myostatin (GDF-8) is a growth and differentiating factor involved in muscle mass regulation during embryonic development and plays a key role in (patho-)physiologic adaptations of skeletal muscle mass [14]. Loss of myostatin function leads to skeletal muscle hypertrophy, hyperplasia and finally a massively increased muscle mass in humans, mice and cattle, with myostatin being highly conserved across species [14,15,16,17]. In contrast, myostatin overexpression has been shown to be involved in muscle atrophy during different diseases such as chronic heart failure or chronic obstructive pulmonary disease [18, 19]. Myostatin mediates atrophy in a Forkhead box O 1 (FoxO1)-dependent manner in vivo and in vitro via upregulation of Atrogin-1 and muscle RING-finger protein-1 (MuRF1) and suppresses muscle protein synthesis reflected by a reduction in myosin heavy chain expression, which is also observed during ICUAW [6, 20]. Myostatin has also been shown to play a role in insulin resistance as it inversely correlates with insulin sensitivity in healthy adults [21, 22]. Furthermore, inhibition of myostatin in murine models has led to improved insulin sensitivity and increased GLUT4 expression, which are both impaired in critically ill patients [11, 23, 24]. Nevertheless, it remains unclear to what extent myostatin is involved in the regulation of muscle atrophy as well as insulin resistance during ICUAW.

Aerobic and resistance exercise have been shown to decrease myostatin levels and improve insulin sensitivity in healthy human subjects [22, 25]. Evidence suggests that this could also be the case in critically ill patients as muscle activation has been shown to restore impaired GLUT4 translocation and prevent muscle atrophy [11, 26]. Early mobilization is generally recommended for critically ill patients due to its beneficial clinical effects [27, 28]. Whether myostatin is involved in the beneficial effects of early mobilization in critically ill patients has not been investigated so far.

Pharmaceutical inhibition of myostatin is possible and has been investigated in different diseases (NCT02310763, NCT02907619). Investigations in critically ill patients have not been conducted as the role of myostatin during critical illness is unknown.

We hypothesized that myostatin mRNA expression and systemic protein levels are elevated during the early and acute phase of critical illness in patients with ICUAW and that this is associated with muscle atrophy, development of CIP and CIM and insulin resistance. We further hypothesized that the beneficial effects of early mobilization are due to a suppression of myostatin rendering pharmaceutical inhibition as a possible prophylactic or therapeutic intervention to improve muscle quality.

Material and methods

Study design

We performed a retrospective analysis in a pooled adult patient cohort that participated in two prospective clinical studies (ISRCTN77569430 [6] and ISRCTN19392591 [26]) conducted in the same ICUs at a tertiary university care center (Charité – Universitätsmedizin Berlin). The first study was an observational study investigating pathomechanisms of ICUAW, while the second study was a randomized controlled interventional trial investigating the effects of protocol-based physiotherapy with and without early muscle activating measures on ICUAW. Patients were enrolled following written informed consent provided by a legal proxy. Ethical approval for both studies had been granted by the institutional review board (EA2/061/06 and EA2/041/10) and conformed to the Declaration of Helsinki.


Patients in both studies fulfilled the same in- and exclusion criteria. The following criteria were necessary for inclusion: age ≥ 18 years, mechanical ventilation, and high risk for developing ICUAW (defined as SOFA score ≥ 9 within the first 72 h after ICU admission). Exclusion criteria encompassed: Body Mass Index > 35 kg/m2, futile prognosis with high likelihood of death in the following hours, previously known neuromuscular disease and/or insulin-dependent diabetes mellitus. For reference values from healthy individuals, muscle biopsy specimens from 11 and plasma samples from 91 healthy volunteers were used. Due to analysis in different laboratory facilities and scarcity of tissue MSTN qPCR was performed in 5 of these 11 volunteers and the other qPCRs as well as histologic investigations were performed in the other 6 volunteers (see Table 1).

Table 1 Baseline characteristics


Patients from the observational studies received standard physiotherapy (sPT) as prescribed by the treating physician. These patients were compared to those in the prospective interventional study that received protocol-based physiotherapy guided by daily mobilization goals that were defined during a multiprofessional ward round. The daily mobilization goals were provided by a stepwise approach starting at level 1 (no mobilization) until level 5 (intensified therapy with activities of daily living). Randomization allocated patients to just protocol-based physiotherapy (pPT) or protocol-based physiotherapy and additional muscle activating measures (pPT + adMeas), meaning neuromuscular electrical stimulation and/or whole-body vibration, daily for 20 min per additional measure, leading to three different groups (standard physiotherapy (sPT), protocol-based physiotherapy (pPT) and protocol-based physiotherapy + muscle activating measures (pPT + adMeas)) that were compared. Further details have been published [26].


All patients underwent surgical muscle biopsy of the M. vastus lateralis 15 days (respectively closest possible day) after ICU admission (Table 1).

Determination of expression levels for MYH1, MYH2, MYH4, CAPN1, CASP3, TRIM62, TRIM63, FBXO32, PSMB2, IL6, TNFalpha and SAA1/2 as well as histologic analysis were performed as described previously [26]. Gene expression for MSTN was performed as outlined in the Additional file 1.

Blood samples were collected from ICU patients on day 4, 8 and 14 (or closest possible day) after ICU admission for determination of myostatin plasma levels. Myostatin plasma concentrations were measured using commercial ELISA (GDF-8/Myostatin Immunoassay; Catalog Number DGDF80, R&D Systems, Minneapolis, USA) (inter-assay CV 3.1–6.0%, intra-assay CV 1.8–5.4%).

Muscle strength was assessed using the Medical Research Council (MRC) score at first adequate awakening and at ICU discharge according to the criteria established by DeJonghe et al. [29]. Diagnosis of ICUAW was confirmed when an average score below 4 across all tested muscles was observed [1].

Electrophysiological evaluations were performed by an experienced neurologist after the first week in the ICU via a portable two-channel Keypoint Medtronic equipment (Skovlunde, Denmark). Patients were categorized into CIM if compound muscle action potential after direct muscle stimulation showed an amplitude below 3.0 mA and CIP when sensory nerve action potential showed a reduced amplitude. If both criteria were fulfilled, patients were categorized into CIM/CIP. Further details have been published [30].

Hyperinsulinemic–euglycemic clamp to determine the insulin sensitivity index was performed as described previously [11].

Subgroup analysis

Patients were categorized according to myostatin plasma levels on day 14 into two subgroups: according to increased/decreased levels when compared to healthy controls.


Categorical variables are shown as counts and percentages, while metric variables are shown as median with interquartile range (IQR). Values for mRNA expression and plasma concentrations were normalized to healthy controls and are shown as fold change. Statistical difference was tested accordingly with a Mann–Whitney U and Kruskal–Wallis test for metric variables and between subject differences, a general linear model for repeated measures for metric variables and within subject differences and a chi-square test for categorical variables. Post hoc comparison of different groups within the general linear model for repeated measures was made applying Bonferroni correction for multiple comparison. Correlation analyses were performed with the Spearman’s rank correlation coefficient. A priori a two-tailed alpha level of < 0.05 was defined to indicate statistical significance. Statistical analysis was performed with SPSS (IBM Corp. SPSS Statistics for Macintosh, Version 26.0. Armonk, NY, USA). Graphs were designed with GraphPad Prism (Version 7.00 for Macintosh, GraphPad Software, La Jolla California USA).


Eighty-three patients (33 from the observational study and 50 from the interventional trial) were included into the study (see Additional file 1: Fig. S1). Baseline characteristics for all patients are shown in Table 1.

Myostatin trajectory

Critically ill patients showed a significantly reduced MSTN gene expression in skeletal muscle when compared to healthy controls (p = 0.004; Fig. 1a). Reduced myostatin plasma levels were observed during the first 2 weeks of the ICU stay (p < 0.001), and were pronounced during the early phase of ICU treatment but with a significant increase over time (p < 0.001; Fig. 1b; see Additional file 1: Table S1 for absolute values). Patients with plasma myostatin levels on day 14 above the levels of healthy controls were significantly younger (see Additional file 1: Table S2).

Fig. 1
figure 1

MSTN gene expression on day 15 and myostatin plasma trajectory. a MSTN gene expression was significantly decreased in critically ill patients (median [IQR] fold change: 1.00 [0.68–1.54] vs. 0.26 [0.11–0.80]; p = 0.004). b Myostatin plasma concentration over time showed significantly decreased values in critically ill patients. A recovery throughout the first 14 days can be observed (GLM median [IQR] fold change: healthy control vs. day 4 vs. day 8 vs. day 14—median [IQR] 0.99 [0.80–1.20] vs. 0.13 [0.08–0.21] vs. 0.23 [0.10–0.44] vs. 0.40 [0.26–0.61]; p < 0.001; n = 36 patients with values from all three timepoints were analyzed). GLM = general linear model for the factor “time” in critically ill; mRNA = messenger ribonucleic acid. ###p < 0.001 for Kruskal–Wallis test between healthy controls and critically ill; ***p < 0.001 for post hoc test comparison with healthy controls

Muscle strength and physical function

Muscular MSTN gene expression on day 15 after ICU admission was significantly lower in ICUAW patients compared to controls and patients without ICUAW, while no difference was detected between controls and patients without ICUAW (Fig. 2a). Patients with and without ICUAW at ICU discharge had significantly decreased myostatin plasma levels, which significantly increased over time. A difference between patients with ICUAW and patients without ICUAW was not observed (Fig. 2b). Low myostatin plasma concentrations on day 8 showed a correlation to reduced muscle strength at first awakening, while no correlation was observed at ICU discharge (correlation coefficient 0.339; R2 = 0.109; p = 0.020; see Additional file 1: Fig. S2, Table S3).

Fig. 2
figure 2

Differences in MSTN gene expression on day 15 and myostatin plasma trajectory in patients diagnosed with ICUAW at ICU discharge. a MSTN gene expression was significantly decreased in all critically ill patients independent of the ICUAW diagnosis. Patients with ICUAW presented furthermore a significant reduction in MSTN gene expression over those without ICUAW. b Myostatin plasma trajectory shows significantly decreased values that recover over time independent of ICUAW, while no differences between patients with and without ICUAW can be observed (GLM: p < 0.001; n = 9 patients with ICUAW and n = 15 without ICUAW with values from all three timepoints were analyzed). GLM = general linear model for the factor “time” in critically ill; mRNA = messenger ribonucleic acid. ###p < 0.001 for Kruskal–Wallis test between healthy controls and critically ill; **p < 0.01 and ***p < 0.001 for post hoc test comparison with healthy controls; +p < 0.05 for post hoc test comparison between critically ill


Compared to healthy controls, MSTN gene expression showed a significant reduction in all critically ill patients regardless of the intervention they were randomized to or the level of mobilization they achieved until muscle biopsy (Fig. 3a, c). Myostatin plasma levels presented a similar pattern for the interventions as well as maximum level of mobilization with a significant reduction in all critically ill patients and a significant recovery over time with no between-group differences (Fig. 3b, d).

Fig. 3
figure 3

Impact of maximum level of mobilization as well as different physiotherapeutic regimens on MSTN gene expression on day 15 and myostatin plasma trajectory. a MSTN gene expression was not influenced by standard physiotherapy (sPT), protocol-based physiotherapy (pPT) or protocol-based physiotherapy with additional muscle activating measures (pPT +) as it was significantly decreased over healthy controls (hc) in all groups. b Myostatin plasma levels showed a similar pattern with decreased values in all critically ill patients independent of the intervention and with a significant recovery of time (GLM: p < 0.001; n = 7 patients receiving sPT, n = 10 receiving pPT and n = 19 receiving pPT + adMeas with values from all three timepoints were analyzed). c MSTN gene expression did not show any difference due to the achieved level of mobilization and neither a reduction over baseline values. d Myostatin plasma trajectory presented similarly without any impact of the achieved level of mobilization but a significant reduction in all critically ill patients. A significant recovery over time was also evident (GLM: p = 0.001; n = 14 patients reaching level 2, n = 10 reaching level 3 and n = 5 reaching level 4 with values from all three timepoints were analyzed). GLM = general linear model for the factor “time” in critically ill; mRNA = messenger ribonucleic acid. #p < 0.050, ##p < 0.010 and ###p < 0.001 for Kruskal–Wallis test between healthy controls and critically ill. *p < 0.05, **p < 0.01 and ***p < 0.001 for post hoc test comparison with healthy controls


MSTN gene expression was decreased in all critically ill patients irrespective of the electrophysiological classification (except in patients with CIP; n.s.). No difference in expression levels between these groups could be observed (see Additional file 1: Fig. S3a). Similarly, myostatin plasma levels were significantly reduced at all timepoints regardless of the electrophysiological classification (see Additional file 1: Fig. S3b). No correlation between compound muscle action potential after direct muscle stimulation (dmCMAP) and neither MSTN gene expression nor myostatin plasma levels were observed (see Additional file 1: Table S4). No patient with myostatin plasma levels higher than healthy controls on day 14 was classified as CIP, CIM or CIP/CIM (see Additional file 1: Fig. S3c).

Muscle homeostasis

Critically ill patients show significantly increased expression levels of genes related to muscle atrophy and inflammation when compared to healthy controls. Myosin protein content and myocyte cross-sectional area were not different according to the myostatin groups (see Additional file 1: Fig. S4a,b).

Insulin sensitivity

Critically ill patients with myostatin plasma levels higher than healthy controls also showed a significantly higher insulin sensitivity index (see Additional file 1: Fig. S5a). In line with that, a direct correlation between the insulin sensitivity index and myostatin plasma levels on day 14 was observed (see Additional file 1: Fig. S5b, Table S5).


Muscular MSTN gene expression and myostatin plasma levels presented a congruent decrease in critically ill patients that increased over time while not reaching baseline values 14 days after ICU admission. MSTN gene expression was significantly lower in patients with clinical weakness. Otherwise, no difference was observed when stratifying patients according to weakness or electrophysiological classification. Markers of muscle atrophy were not associated with myostatin plasma levels. The association of myostatin plasma levels and insulin resistance was contrary to our hypothesis with decreased values in patient with more severe insulin resistance. No effect of early mobilization or additional muscle activating measure on neither myostatin plasma levels nor MSTN gene expression could be observed.

Previous studies indicate interest in therapeutic modulation of myostatin as an established regulator of muscle mass. It was hypothesized that inhibition of myostatin could ameliorate muscle atrophy and improve muscle function [14, 31]. Multiple therapeutic options such as myostatin-binding proteins or myostatin-neutralizing antibodies have been developed and tested [32, 33]. We have therefore included plasma values into our study to be able to establish a rationale for the application of these inhibitors in ICUAW and to identify a potential biomarker. However, published results in hereditary muscle disease were rather disappointing and previous trials had to be discontinued partly due to adverse events and lack of efficacy (NCT02310763, NCT02907619) [34].

Contrary to the substantially increased muscle mass in animals and humans with genetic alterations leading to lacking myostatin effect did anti-myostatin therapy in hereditary muscle disease not lead to an increase in muscle mass [35]. Mariot et al. investigated the causes for these diverging observations [35]. The authors showed that patients with Duchenne muscular dystrophy as well as spinal muscular atrophy have reduced levels of both systemic myostatin and activin (also a negative regulator of muscle mass from the TGF-beta superfamily) while typically having increased levels of circulating follistatin as an important inhibitor of myostatin leading to muscle growth [35, 36]. Moreover, they found that the same patients with Duchenne muscular dystrophy also have reduced myostatin expression levels in skeletal muscle [35]. Furthermore, patients with inclusion body myositis show not only reduced myostatin expression levels in skeletal muscle but also an increased follistatin expression [35]. These findings are in line with our data from critically ill patients, data from a murine sepsis model from Smith et al., and the findings presented by Burch et al. in patients with genetic neuromuscular disorders [37,38,39]. Additionally, Puthucheary et al. identified no change over time in MSTN gene expression in critically ill patients between ICU day 1 and 7, while it remains unclear if the values were reduced due to a lacking comparison with healthy controls [8]. These findings diverge from ours as the group did not observe recovery over time, which might be an effect of sample size as Wirtz et al. also observed significantly reduced myostatin plasma levels [39]. In agreement with the data and interpretation of Mariot et al., we hypothesize that the myostatin downregulation could be a compensatory mechanism to muscle atrophy induced by the underlying muscular disease [35]. These findings are underlined by the fact that Mariot et al. observed an upregulation of follistatin, which has an antagonistic effect on myostatin and leads to muscle growth [35].

Interestingly, respective compensatory mechanisms could be hampered during critical illness as it may dependent on the insulin-like growth factor receptor. In their work, Kalista et al. observed that the hypertrophic effect of follistatin is mediated via the IGF-I receptor/Akt/mTOR pathway [40]. Previously, it was shown that the IGF-I receptor gene expression is significantly reduced in critically ill patients, especially those with CIM, which may blunt compensatory mechanisms [11]. Furthermore, we observed reduced mTOR protein levels in critically ill patients, which is also involved in the hypertrophic effect elicited by follistatin [11].

Myostatin increases the expression of MuRF1 and Atrogin-1 as key mediators of muscle atrophy and decreases the expression of myosin heavy chain [20]. Contrary to our hypothesis were MuRF1, Atrogin-1 and/or myosin heavy chains appeared not to be associated with myostatin. The recent literature demonstrated an early increase in muscle protein synthesis in critically ill patients measured via labeled amino acids. This might be a result of the compensatory downregulation of myostatin [10].

The compensatory downregulation could also extend beyond muscle atrophy into insulin signaling as insulin resistance is a common observation during critical illness and high myostatin levels have also been associated with insulin resistance [21, 22]. Evidence suggests that myostatin might mediate insulin resistance in a similar fashion that was observed during critical illness, namely decreased GLUT4 expression and translocation [11, 41]. The direct correlation observed between myostatin and the insulin sensitivity index in critically ill patients is inverse to the correlation observed in healthy adults and might be a product of compensatory downregulation in order to improve insulin sensitivity in the critically ill patients [21].

It appears that the TGF-beta pathway while not being regulated via myostatin plays a critical role in ICUAW. Bloch et al. have shown that GDF-15, a myokine from the TGF-beta family similar to myostatin, is upregulated during critical illness [42]. This observation underlines that the atrophy mechanism during ICUAW is different from COPD as both myostatin and GDF-15 were increased in COPD patients [43].

Exercise is a powerful stimulus to increase muscle mass and function [44]. It has been shown to be linked to myostatin as plasma, muscle protein and muscle expression levels significantly decreased with exercise [22, 45]. We hypothesized that early mobilization mediates its beneficial effects on muscle mass via myostatin. However, we did not observe any effects of the mobilization strategies tested, such as protocol-based physiotherapy with and without muscle activating measures, nor of different levels of mobilization during the ICU stay, for example whether the patients achieved ambulation or not, on myostatin plasma levels or gene expression.

Nonetheless, our study has certain limitations. First, driven by study design, pooled data (which were recorded in a prospective fashion) from two independent clinical studies were analyzed retrospectively. Secondly, all patients were recruited within one academic center, which might hamper external validity. Third, driven by the observational nature of our investigations, further investigations are required to elucidate potential mechanism behind the downregulation of myostatin. As this was out of the scope of the current analysis, it should be pursued in subsequent studies. Last, due to the complex nature of the study with molecular analyses from biological samples in critically ill patients we have some missing values in certain analyses, which limits external validity of the results.


Data from two prospective clinical studies demonstrate that myostatin gene expression and systemic protein levels are significantly decreased in critically ill patients with ICUAW. We conclude from our data that myostatin is likely not a key driver of muscle weakness, muscle atrophy, insulin resistance and/or electrophysiological alterations observed during critical illness. Improving muscle quality via therapeutic inhibition of myostatin to prevent or treat muscle weakness, muscle atrophy and/or insulin resistance during critical illness does not seem to have a robust pathophysiological rationale.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.



Protein kinase b


Acute respiratory distress syndrome






Critical illness myopathy


Critical illness polyneuropathy


Central nervous system


Direct muscle stimulation compound muscle action potential


Enzyme-linked immunosorbent assay

FBXO32 :

F-box protein 32


Forkhead box O1 (FoxO1)




Glucose transporter type 4


Intensive care unit


Intensive care unit-acquired weakness


Insulin-like growth factor I

IL6 :

Interleukin 6


Interquartile range


Medical Research Council score


Messenger ribonucleic acid


Myostatin gene


Mammalian target of rapamycin

MuRF-1 :

Muscle RING-finger protein-1

MYH1 :

Myosin heavy chain 1

MYH2 :

Myosin heavy chain 2

MYH4 :

Myosin heavy chain 3


Protocol-based physiotherapy

pPT + adMeas:

Protocol-based physiotherapy + additional muscle activating measures


Proteasome 20S Subunit Beta 2


Quantitative polymerase chain reaction


Richmond agitation sedation


Sepsis-related Organ Failure Assessment Score


Standard physiotherapy


Transforming growth factor beta 1

TNFalpha :

Tumor necrosis factor alpha

TRIM62 :

Tripartite motif-containing 62

TRIM63 :

Tripartite motif-containing 63

SAA1/2 :

Serum amyloid ½


  1. Fan E, Cheek F, Chlan L, Gosselink R, Hart N, Herridge MS, Hopkins RO, Hough CL, Kress JP, Latronico N, et al. An official American Thoracic Society Clinical Practice guideline: the diagnosis of intensive care unit-acquired weakness in adults. Am J Respir Crit Care Med. 2014;190(12):1437–46.

    PubMed  Article  Google Scholar 

  2. Appleton RT, Kinsella J, Quasim T. The incidence of intensive care unit-acquired weakness syndromes: a systematic review. J Intensive Care Soc. 2015;16(2):126–36.

    PubMed  Article  Google Scholar 

  3. Schefold JC, Wollersheim T, Grunow JJ, Luedi MM, Z’Graggen WJ, Weber-Carstens S. Muscular weakness and muscle wasting in the critically ill. J Cachexia Sarcopenia Muscle. 2020;11(6):1399–412.

    PubMed  PubMed Central  Article  Google Scholar 

  4. Hermans G, Van Mechelen H, Clerckx B, Vanhullebusch T, Mesotten D, Wilmer A, Casaer MP, Meersseman P, Debaveye Y, Van Cromphaut S, et al. Acute outcomes and 1-year mortality of intensive care unit-acquired weakness. A cohort study and propensity-matched analysis. Am J Respir Crit Care Med. 2014;190(4):410–20.

    PubMed  Article  Google Scholar 

  5. Van Aerde N, Meersseman P, Debaveye Y, Wilmer A, Gunst J, Casaer MP, Bruyninckx F, Wouters PJ, Gosselink R, Van den Berghe G, et al. Five-year impact of ICU-acquired neuromuscular complications: a prospective, observational study. Intensive Care Med. 2020;46:1184–93.

    PubMed  Article  CAS  Google Scholar 

  6. Wollersheim T, Woehlecke J, Krebs M, Hamati J, Lodka D, Luther-Schroeder A, Langhans C, Haas K, Radtke T, Kleber C, et al. Dynamics of myosin degradation in intensive care unit-acquired weakness during severe critical illness. Intensive Care Med. 2014;40(4):528–38.

    CAS  PubMed  Article  Google Scholar 

  7. Helliwell TR, Wilkinson A, Griffiths RD, McClelland P, Palmer TE, Bone JM. Muscle fibre atrophy in critically ill patients is associated with the loss of myosin filaments and the presence of lysosomal enzymes and ubiquitin. Neuropathol Appl Neurobiol. 1998;24(6):507–17.

    CAS  PubMed  Article  Google Scholar 

  8. Puthucheary ZA, Rawal J, McPhail M, Connolly B, Ratnayake G, Chan P, Hopkinson NS, Phadke R, Dew T, Sidhu PS, et al. Acute skeletal muscle wasting in critical illness. JAMA. 2013;310(15):1591–600.

    CAS  PubMed  Article  Google Scholar 

  9. Dos Santos C, Hussain SN, Mathur S, Picard M, Herridge M, Correa J, Bain A, Guo Y, Advani A, Advani SL, et al. Mechanisms of chronic muscle wasting and dysfunction after an intensive care unit stay. A pilot study. Am J Respir Crit Care Med. 2016;194(7):821–30.

    PubMed  Article  Google Scholar 

  10. Klaude M, Mori M, Tjader I, Gustafsson T, Wernerman J, Rooyackers O. Protein metabolism and gene expression in skeletal muscle of critically ill patients with sepsis. Clin Sci (Lond). 2012;122(3):133–42.

    CAS  Article  Google Scholar 

  11. Weber-Carstens S, Schneider J, Wollersheim T, Assmann A, Bierbrauer J, Marg A, Al Hasani H, Chadt A, Wenzel K, Koch S, et al. Critical illness myopathy and GLUT4: significance of insulin and muscle contraction. Am J Respir Crit Care Med. 2013;187(4):387–96.

    CAS  PubMed  Article  Google Scholar 

  12. Hermans G, Schrooten M, Van Damme P, Berends N, Bouckaert B, De Vooght W, Robberecht W, Van den Berghe G. Benefits of intensive insulin therapy on neuromuscular complications in routine daily critical care practice: a retrospective study. Crit Care. 2009;13(1):R5.

    PubMed  PubMed Central  Article  Google Scholar 

  13. van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359–67.

    PubMed  Article  Google Scholar 

  14. McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature. 1997;387(6628):83–90.

    CAS  PubMed  Article  Google Scholar 

  15. Schuelke M, Wagner KR, Stolz LE, Hubner C, Riebel T, Komen W, Braun T, Tobin JF, Lee SJ. Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med. 2004;350(26):2682–8.

    CAS  PubMed  Article  Google Scholar 

  16. Grobet L, Martin LJ, Poncelet D, Pirottin D, Brouwers B, Riquet J, Schoeberlein A, Dunner S, Menissier F, Massabanda J, et al. A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle. Nat Genet. 1997;17(1):71–4.

    CAS  PubMed  Article  Google Scholar 

  17. McPherron AC, Lee SJ. Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci USA. 1997;94(23):12457–61.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. Hayot M, Rodriguez J, Vernus B, Carnac G, Jean E, Allen D, Goret L, Obert P, Candau R, Bonnieu A. Myostatin up-regulation is associated with the skeletal muscle response to hypoxic stimuli. Mol Cell Endocrinol. 2011;332(1–2):38–47.

    CAS  PubMed  Article  Google Scholar 

  19. George I, Bish LT, Kamalakkannan G, Petrilli CM, Oz MC, Naka Y, Sweeney HL, Maybaum S. Myostatin activation in patients with advanced heart failure and after mechanical unloading. Eur J Heart Fail. 2010;12(5):444–53.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Aravena J, Abrigo J, Gonzalez F, Aguirre F, Gonzalez A, Simon F, Cabello-Verrugio C. Angiotensin (1–7) decreases myostatin-induced NF-kappaB signaling and skeletal muscle atrophy. Int J Mol Sci. 2020;21(3):1167.

    CAS  PubMed Central  Article  Google Scholar 

  21. Amor M, Itariu BK, Moreno-Viedma V, Keindl M, Jurets A, Prager G, Langer F, Grablowitz V, Zeyda M, Stulnig TM. Serum myostatin is upregulated in obesity and correlates with insulin resistance in humans. Exp Clin Endocrinol Diabetes. 2019;127(8):550–6.

    CAS  PubMed  Article  Google Scholar 

  22. Hittel DS, Axelson M, Sarna N, Shearer J, Huffman KM, Kraus WE. Myostatin decreases with aerobic exercise and associates with insulin resistance. Med Sci Sports Exerc. 2010;42(11):2023–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Coleman SK, Rebalka IA, D’Souza DM, Deodhare N, Desjardins EM, Hawke TJ. Myostatin inhibition therapy for insulin-deficient type 1 diabetes. Sci Rep. 2016;6:32495.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Dong J, Dong Y, Dong Y, Chen F, Mitch WE, Zhang L. Inhibition of myostatin in mice improves insulin sensitivity via irisin-mediated cross talk between muscle and adipose tissues. Int J Obes (Lond). 2016;40(3):434–42.

    CAS  Article  Google Scholar 

  25. Jespersen JG, Nedergaard A, Andersen LL, Schjerling P, Andersen JL. Myostatin expression during human muscle hypertrophy and subsequent atrophy: increased myostatin with detraining. Scand J Med Sci Sports. 2011;21(2):215–23.

    CAS  PubMed  Article  Google Scholar 

  26. Wollersheim T, Grunow JJ, Carbon NM, Haas K, Malleike J, Ramme SF, Schneider J, Spies CD, Mardian S, Mai K, et al. Muscle wasting and function after muscle activation and early protocol-based physiotherapy: an explorative trial. J Cachexia Sarcopenia Muscle. 2019;10:734–47.

    PubMed  PubMed Central  Article  Google Scholar 

  27. Bein T, Bischoff M, Bruckner U, Gebhardt K, Henzler D, Hermes C, Lewandowski K, Max M, Nothacker M, Staudinger T, et al. S2e guideline: positioning and early mobilisation in prophylaxis or therapy of pulmonary disorders : revision 2015: S2e guideline of the German Society of Anaesthesiology and Intensive Care Medicine (DGAI). Anaesthesist. 2015;64(Suppl 1):1–26.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. Schaller SJ, Anstey M, Blobner M, Edrich T, Grabitz SD, Gradwohl-Matis I, Heim M, Houle T, Kurth T, Latronico N, et al. Early, goal-directed mobilisation in the surgical intensive care unit: a randomised controlled trial. Lancet. 2016;388(10052):1377–88.

    PubMed  Article  Google Scholar 

  29. De Jonghe B, Sharshar T, Lefaucheur JP, Authier FJ, Durand-Zaleski I, Boussarsar M, Cerf C, Renaud E, Mesrati F, Carlet J, et al. Paresis acquired in the intensive care unit: a prospective multicenter study. JAMA. 2002;288(22):2859–67.

    PubMed  Article  Google Scholar 

  30. Koch S, Spuler S, Deja M, Bierbrauer J, Dimroth A, Behse F, Spies CD, Wernecke KD, Weber-Carstens S. Critical illness myopathy is frequent: accompanying neuropathy protracts ICU discharge. J Neurol Neurosurg Psychiatry. 2011;82(3):287–93.

    PubMed  Article  Google Scholar 

  31. Cohen S, Nathan JA, Goldberg AL. Muscle wasting in disease: molecular mechanisms and promising therapies. Nat Rev Drug Discov. 2015;14(1):58–74.

    CAS  PubMed  Article  Google Scholar 

  32. Zhou X, Wang JL, Lu J, Song Y, Kwak KS, Jiao Q, Rosenfeld R, Chen Q, Boone T, Simonet WS, et al. Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell. 2010;142(4):531–43.

    CAS  PubMed  Article  Google Scholar 

  33. Murphy KT, Cobani V, Ryall JG, Ibebunjo C, Lynch GS. Acute antibody-directed myostatin inhibition attenuates disuse muscle atrophy and weakness in mice. J Appl Physiol (1985). 2011;110(4):1065–72.

    CAS  Article  Google Scholar 

  34. Campbell C, McMillan HJ, Mah JK, Tarnopolsky M, Selby K, McClure T, Wilson DM, Sherman ML, Escolar D, Attie KM. Myostatin inhibitor ACE-031 treatment of ambulatory boys with Duchenne muscular dystrophy: results of a randomized, placebo-controlled clinical trial. Muscle Nerve. 2017;55(4):458–64.

    CAS  PubMed  Article  Google Scholar 

  35. Mariot V, Joubert R, Hourde C, Feasson L, Hanna M, Muntoni F, Maisonobe T, Servais L, Bogni C, Le Panse R, et al. Downregulation of myostatin pathway in neuromuscular diseases may explain challenges of anti-myostatin therapeutic approaches. Nat Commun. 2017;8(1):1859.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  36. Latres E, Mastaitis J, Fury W, Miloscio L, Trejos J, Pangilinan J, Okamoto H, Cavino K, Na E, Papatheodorou A, et al. Activin A more prominently regulates muscle mass in primates than does GDF8. Nat Commun. 2017;8:15153.

    PubMed  PubMed Central  Article  Google Scholar 

  37. Smith IJ, Aversa Z, Alamdari N, Petkova V, Hasselgren PO. Sepsis downregulates myostatin mRNA levels without altering myostatin protein levels in skeletal muscle. J Cell Biochem. 2010;111(4):1059–73.

    CAS  PubMed  Article  Google Scholar 

  38. Burch PM, Pogoryelova O, Palandra J, Goldstein R, Bennett D, Fitz L, Guglieri M, Bettolo CM, Straub V, Evangelista T, et al. Reduced serum myostatin concentrations associated with genetic muscle disease progression. J Neurol. 2017;264(3):541–53.

    CAS  PubMed  Article  Google Scholar 

  39. Wirtz TH, Loosen SH, Buendgens L, Kurt B, Abu Jhaisha S, Hohlstein P, Brozat JF, Weiskirchen R, Luedde T, Tacke F, et al. Low myostatin serum levels are associated with poor outcome in critically ill patients. Diagnostics (Basel). 2020;10(8):574.

    CAS  Article  Google Scholar 

  40. Kalista S, Schakman O, Gilson H, Lause P, Demeulder B, Bertrand L, Pende M, Thissen JP. The type 1 insulin-like growth factor receptor (IGF-IR) pathway is mandatory for the follistatin-induced skeletal muscle hypertrophy. Endocrinology. 2012;153(1):241–53.

    CAS  PubMed  Article  Google Scholar 

  41. Liu XH, Bauman WA, Cardozo CP. Myostatin inhibits glucose uptake via suppression of insulin-dependent and -independent signaling pathways in myoblasts. Physiol Rep. 2018;6(17): e13837.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  42. Bloch SA, Lee JY, Syburra T, Rosendahl U, Griffiths MJ, Kemp PR, Polkey MI. Increased expression of GDF-15 may mediate ICU-acquired weakness by down-regulating muscle microRNAs. Thorax. 2015;70(3):219–28.

    CAS  PubMed  Article  Google Scholar 

  43. Patel MS, Lee J, Baz M, Wells CE, Bloch S, Lewis A, Donaldson AV, Garfield BE, Hopkinson NS, Natanek A, et al. Growth differentiation factor-15 is associated with muscle mass in chronic obstructive pulmonary disease and promotes muscle wasting in vivo. J Cachexia Sarcopenia Muscle. 2016;7(4):436–48.

    PubMed  Article  Google Scholar 

  44. Schaller SJ, Nagashima M, Schonfelder M, Sasakawa T, Schulz F, Khan MAS, Kem WR, Schneider G, Schlegel J, Lewald H, et al. GTS-21 attenuates loss of body mass, muscle mass, and function in rats having systemic inflammation with and without disuse atrophy. Pflugers Arch. 2018;470(11):1647–57.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Louis E, Raue U, Yang Y, Jemiolo B, Trappe S. Time course of proteolytic, cytokine, and myostatin gene expression after acute exercise in human skeletal muscle. J Appl Physiol (1985). 2007;103(5):1744–51.

    CAS  Article  Google Scholar 

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Open Access funding enabled and organized by Projekt DEAL. Julius J. Grunow is participant in the BIH-Charité Junior Clinician Scientist Program, and Tobias Wollersheim was participant in the BIH-Charité Clinician Scientist Program during the study funded by the Charité – Universitätsmedizin Berlin and the Berlin Institute of Health. The Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) to Jens Fielitz: FI 965/5-1, FI 965/5-2, FI 965/9-1; to Steffen Weber-Carstens: KFO-192. DZHK (German Center for Cardiovascular Research), partner site Greifswald, 81Z5400153.

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Authors and Affiliations



KM, JF, JS, SWC and TW developed the study concept; JG, KR, NMC, KM, SK, JF, JS, SWC and TW performed the study and data acquisition; JG, KR, KM, JF, JS, SWC and TW performed the data analysis; JG, KR, KM, JF, JS, SWC and TW interpreted the analyzed data; JG and TW wrote the first draft of the manuscript. All authors critically revised the first draft of the manuscript for important intellectual content. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Steffen Weber-Carstens.

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Ethics approval and consent to participate

Ethical approval for both studies had been granted by the institutional review board (EA2/061/06 and EA2/041/10) and conformed to the Declaration of Helsinki. Patients were included after written informed consent by a legal proxy.

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Not applicable.

Competing interests

SJ Schaller reports grants and non-financial support from ESICM (Brussels, Belgium), Fresenius (Germany), Liberate Medical LLC (Crestwood, USA), STIMIT AG (Nidau, Switzerland), MSD (Haar, Germany) as well as from Technical University of Munich, Germany, from national (e.g., DGAI) and international (e.g., ESICM) medical societies (or their congress organizers) in the field of anesthesiology and intensive care, all outside the submitted work; SJS holds stocks in small amounts from Alphabet Inc., Bayer AG, Rhön-Klinikum AG, and Siemens AG. These did not have any influence on this study. JCS reports (full departmental disclosure) grants from Orion Pharma, Abbott Nutrition International, B. Braun Medical AG, CSEM AG, Edwards Lifesciences Services GmbH, Kenta Biotech Ltd., Maquet Critical Care AB, Omnicare Clinical Research AG, Nestle, Pierre Fabre Pharma AG, Pfizer, Bard Medica S.A., Abbott AG, Anandic Medical Systems, Pan Gas AG Healthcare, Bracco, Hamilton Medical AG, Fresenius Kabi, Getinge Group Maquet AG, Dräger AG, Teleflex Medical GmbH, Glaxo Smith Kline, Merck Sharp and Dohme AG, Eli Lilly and Company, Baxter, Astellas, Astra Zeneca, CSL Behring, Novartis, Covidien, Nycomed, and Phagenesis, outside of the submitted work. The money went into departmental funds, no personal financial gain applies. SWC reports scientific grants from Drägerwerk AG & Co. KGaA, outside of the submitted work.

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Grunow, J.J., Reiher, K., Carbon, N.M. et al. Muscular myostatin gene expression and plasma concentrations are decreased in critically ill patients. Crit Care 26, 237 (2022).

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  • Myostatin
  • Muscle atrophy
  • Insulin resistance
  • Critical illness