Activin A level is associated with physical function in critically ill patients

Published:December 12, 2022DOI:



      Activin A is a potent negative regulator of muscle mass elevated in critical illness. It is unclear whether muscle strength and physical function in critically ill humans are associated with elevated activin A levels.


      The objective of this study was to investigate the relationship between serum activin A levels, muscle strength, and physical function at discharge from the intensive care unit (ICU) and hospital.


      Thirty-six participants were recruited from two tertiary ICUs in Melbourne, Australia. Participants were included if they were mechanically ventilated for >48 h and expected to have a total ICU stay of >5 days. The primary outcome measure was the Six-Minute Walk Test distance at hospital discharge. Secondary outcome measures included handgrip strength, Medical Research Council Sum Score, Physical Function ICU Test Scored, Six-Minute Walk Test, and Timed Up and Go Test assessed throughout the hospital admission. Total serum activin A levels were measured daily in the ICU.


      High peak activin A was associated with worse Six-Minute Walk Test distance at hospital discharge (linear regression coefficient, 95% confidence interval, p-value: −91.3, −154.2 to −28.4, p = 0.007, respectively). Peak activin A concentration was not associated with the secondary outcome measures.


      Higher peak activin A may be associated with the functional decline of critically ill patients. Further research is indicated to examine its potential as a therapeutic target and a prospective predictor for muscle wasting in critical illness.

      Study registration



      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Australian Critical Care
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Puthucheary Z.A.
        • Rawal J.
        • McPhail M.
        • Connolly B.
        • Ratnayake G.
        • Chan P.
        • et al.
        Acute skeletal muscle wasting in critical illness.
        JAMA. Oct 16 2013; 310: 1591-1600
        • Sheean P.M.
        • Peterson S.J.
        • Gomez Perez S.
        • Troy K.L.
        • Patel A.
        • Sclamberg J.S.
        • et al.
        The prevalence of sarcopenia in patients with respiratory failure classified as normally nourished using computed tomography and subjective global assessment.
        J Parenter Enter Nutr. 2014; 38: 873-879
        • Hayes K.
        • Holland A.E.
        • Pellegrino V.A.
        • Mathur S.
        • Hodgson C.L.
        Acute skeletal muscle wasting and relation to physical function in patients requiring extracorporeal membrane oxygenation (ECMO).
        J Crit Care. Dec 2018; 48: 1-8
        • Mayer K.P.
        • Thompson Bastin M.L.
        • Montgomery-Yates A.A.
        • Pastva A.M.
        • Dupont-Versteegden E.E.
        • Parry S.M.
        • et al.
        Acute skeletal muscle wasting and dysfunction predict physical disability at hospital discharge in patients with critical illness.
        Crit Care. 2020/11/04 2020; 24: 637
        • Dos Santos C.
        • Hussain S.N.
        • Mathur S.
        • Picard M.
        • Herridge M.
        • Correa J.
        • et al.
        Mechanisms of chronic muscle wasting and dysfunction after an intensive care unit stay. A pilot study.
        Am J Respir Crit Care Med. Oct 01 2016; 194: 821-830
        • Chan K.S.
        • Mourtzakis M.
        • Friedman L.A.
        • Dinglas V.D.
        • Hough C.L.
        • Ely E.W.
        • et al.
        Evaluating muscle mass in survivors of ARDS: a 1-year multi-center longitudinal study.
        Crit Care Med. 2018; 46: 1238
        • Schiaffino S.
        • Dyar K.A.
        • Ciciliot S.
        • Blaauw B.
        • Sandri M.
        Mechanisms regulating skeletal muscle growth and atrophy.
        FEBS J. Sep 2013; 280: 4294-4314
        • Zhou X.
        • Wang J.
        • Lu J.
        • Song Y.
        • Kwak K.S.
        • Jiao Q.
        • et al.
        Reversal of Cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival.
        Cell. 2010; 142: 531-543
        • Lokireddy S.
        • Mouly V.
        • Butler-Browne G.
        • Gluckman P.D.
        • Sharma M.
        • Kambadur R.
        • et al.
        Myostatin promotes the wasting of human myoblast cultures through promoting ubiquitin-proteasome pathway-mediated loss of sarcomeric proteins.
        Am J Physiol Cell Physiol. 2011; 301: C1316-C1324
        • Marino F.E.
        • Risbridger G.
        • Gold E.
        Activin-βC modulates cachexia by repressing the ubiquitin-proteasome and autophagic degradation pathways.
        J Cachexia Sarcopenia Muscle. 2015; 6: 365-380
        • Evans W.J.
        • Hellerstein M.
        • Orwoll E.
        • Cummings S.
        • Cawthon P.M.
        D3-Creatine dilution and the importance of accuracy in the assessment of skeletal muscle mass.
        J Cachexia Sarcopenia Muscle. 2019; 10: 14-21
        • Needham D.M.
        • Sepulveda K.A.
        • Dinglas V.D.
        • Chessare C.M.
        • Friedman L.A.
        • Bingham III, C.O.
        • et al.
        Core outcome measures for clinical research in acute respiratory failure survivors. An international modified Delphi consensus study.
        Am J Respir Crit Care Med. Nov 1 2017; 196: 1122-1130
        • Michel U.
        • Ebert S.
        • Phillips D.
        • Nau R.
        Serum concentrations of activin and follistatin are elevated and run in parallel in patients with septicemia.
        Eur J Endocrinol. May 2003; 148: 559-564
        • Lee J.K.
        • Choi S.M.
        • Lee J.
        • Park Y.S.
        • Lee C.H.
        • Yim J.J.
        • et al.
        Serum activin-A as a predictive and prognostic marker in critically ill patients with sepsis.
        Respirology. 2016; 21: 891-897
        • Kim J.-M.
        • Lee J.-K.
        • Choi S.M.
        • Lee J.
        • Park Y.S.
        • Lee C.H.
        • et al.
        Diagnostic and prognostic values of serum activin-a levels in patients with acute respiratory distress syndrome.
        BMC Pulm Med. 2019/06/25 2019; 19: 115
        • Synolaki E.
        • Papadopoulos V.
        • Divolis G.
        • Tsahouridou O.
        • Gavriilidis E.
        • Loli G.
        • et al.
        The Activin/follistatin-axis is severely deregulated in COVID-19 and independently associated with in-hospital mortality.
        J Infect Dis. 2021; 223: 1544-1554
        • Linko R.
        • Hedger M.P.
        • Pettilä V.
        • Ruokonen E.
        • Ala-Kokko T.
        • Ludlow H.
        • et al.
        Serum activin A and B, and follistatin in critically ill patients with influenza A (H1N1) infection.
        BMC Infect Dis. 2014; 14: 253
        • de Kretser D.M.
        • Bensley J.G.
        • Pettila V.
        • Linko R.
        • Hedger M.P.
        • Hayward S.
        • et al.
        Serum activin A and B levels predict outcome in patients with acute respiratory failure: a prospective cohort study.
        Crit Care. Oct 31 2013; 17: R263
        • Von Elm E.
        • Altman D.G.
        • Egger M.
        • Pocock S.J.
        • Gøtzsche P.C.
        • Vandenbroucke J.P.
        • et al.
        The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.
        Prev Med. 2007; 45: 247-251
        • Knaus W.A.
        • Draper E.A.
        • Wagner D.P.
        • Zimmerman J.E.
        APACHE II: a severity of disease classification system.
        Crit Care Med. 1985; 13: 818-829
      1. Australian and New Zealand intensive care Society. ANZICS adult patient database 2020, data dictionary [Accessed 14 June 2020].

        • Vincent J.-L.
        • Moreno R.
        • Takala J.
        • Willatts S.
        • De Mendonça A.
        • Bruining H.
        • et al.
        The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure.
        Springer-Verlag, 1996
        • Denehy L.
        • Skinner E.H.
        • Edbrooke L.
        • Haines K.
        • Warrillow S.
        • Hawthorne G.
        • et al.
        Exercise rehabilitation for patients with critical illness: a randomized controlled trial with 12 months of follow-up.
        Crit Care. Jul 24 2013; 17: R156
        • Kleyweg R.P.
        • Van Der Meché F.G.
        • Schmitz P.I.
        Interobserver agreement in the assessment of muscle strength and functional abilities in Guillain-Barré syndrome.
        Muscle Nerve. 1991; 14: 1103-1109
        • Baldwin C.E.
        • Paratz J.D.
        • Bersten A.D.
        Muscle strength assessment in critically ill patients with handheld dynamometry: an investigation of reliability, minimal detectable change, and time to peak force generation.
        J Crit Care. Feb 2013; 28: 77-86
        • Denehy L.
        • de Morton N.A.
        • Skinner E.H.
        • Edbrooke L.
        • Haines K.
        • Warrillow S.
        • et al.
        A physical function test for use in the intensive care unit: validity, responsiveness, and predictive utility of the physical function ICU test (scored).
        Phys Ther. Dec 2013; 93: 1636-1645
        • Podsiadlo D.
        • Richardson S.
        The timed “up & go”: a test of basic functional mobility for frail elderly persons.
        J Am Geriatr Soc. Feb 1991; 39: 142-148
        • ATS
        ATS statement: guidelines for the six-minute walk test.
        Am J Respir Crit Care Med. Jul 1 2002; 166: 111-117
        • Batt J.
        • dos Santos C.C.
        • Cameron J.I.
        • Herridge M.S.
        Intensive care unit-acquired weakness: clinical phenotypes and molecular mechanisms.
        Am J Respir Crit Care Med. Feb 01 2013; 187: 238-246
        • García-Martínez M.Á.
        • González J.C.M.
        • García-de-Lorenzo A.
        • Teijeira S.
        Muscle weakness: understanding the principles of myopathy and neuropathy in the critically ill patient and the management options.
        Clin Nutr. 2020; 39: 1331-1344
        • Tiao G.
        • Hobler S.
        • Wang J.J.
        • Meyer T.A.
        • Luchette F.A.
        • Fischer J.E.
        • et al.
        Sepsis is associated with increased mRNAs of the ubiquitin-proteasome proteolytic pathway in human skeletal muscle.
        J Clin Investig. 1997; 99: 163-168
        • Constantin D.
        • McCullough J.
        • Mahajan R.P.
        • Greenhaff P.L.
        Novel events in the molecular regulation of muscle mass in critically ill patients.
        J Physiol. Aug 1 2011; 589: 3883-3895
        • Schmidt F.
        • Kny M.
        • Zhu X.
        • Wollersheim T.
        • Persicke K.
        • Langhans C.
        • et al.
        The E3 ubiquitin ligase TRIM62 and inflammation-induced skeletal muscle atrophy.
        Crit Care. 2014; 18: 545
        • Mofarrahi M.
        • Sigala I.
        • Guo Y.
        • Godin R.
        • Davis E.C.
        • Petrof B.
        • et al.
        Autophagy and skeletal muscles in sepsis.
        PLoS One. 2012; 7
        • Helliwell T.R.
        • Wilkinson A.
        • Griffiths R.D.
        • McClelland P.
        • Palmer T.E.
        • Bone J.M.
        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. Dec 1998; 24: 507-517
        • Levine S.
        • Nguyen T.
        • Taylor N.
        • Friscia M.E.
        • Budak M.T.
        • Rothenberg P.
        • et al.
        Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans.
        N Engl J Med. 2008; 358: 1327-1335
        • Attie K.M.
        • Borgstein N.G.
        • Yang Y.
        • Condon C.H.
        • Wilson D.M.
        • Pearsall A.E.
        • et al.
        A single ascending-dose study of muscle regulator ACE-031 in healthy volunteers.
        Muscle Nerve. 2013; 47: 416-423
        • Polkey M.I.
        • Praestgaard J.
        • Berwick A.
        • Franssen F.M.
        • Singh D.
        • Steiner M.C.
        • et al.
        Activin type II receptor blockade for treatment of muscle depletion in chronic obstructive pulmonary disease. A randomized trial.
        Am J Respir Crit Care Med. 2019; 199: 313-320
      2. Study of muscle effects of BYM338 in mechanically ventilated patients.