Skip to main content
SpringerLink
Log in

Muscle Weakness, Molecular Mechanism, and Nutrition During Critical Illness

  • Living reference work entry
  • First Online:
Diet and Nutrition in Critical Care

  • 113 Accesses

Abstract

Muscle weakness develops in a substantial proportion of critically ill patients. The consequences are severe, as illustrated by a prolonged dependency on mechanical ventilation and intensive care, impaired rehabilitation, and increased risk of death. Muscle weakness may originate from neurogenic disturbances, myogenic disturbances, or a combination of both.

Regarding the myogenic component of muscle weakness, loss of muscle mass or atrophy has classically been put forward as culprit, whereas the importance of muscle quality has long been underappreciated and only recently has gained attention. Muscle atrophy of critical illness develops due to a decreased synthesis and accelerated breakdown of myofibrillar proteins. Several proteolytic systems are activated, including the ubiquitin-proteasome pathway, calpains, and lysosomal proteases. Also excessive activation of autophagy, which is a highly specialized lysosomal degradation pathway with a crucial role in intracellular quality control, has been implicated in the aggravation of muscle loss. Nevertheless, recent studies suggest that impairment of autophagy jeopardizes muscle quality and function and that autophagy may be insufficiently activated during critical illness.

Illness-associated anorexia and gastrointestinal dysfunction often lead to a severe caloric deficit, which contributes to muscle atrophy. This raised the hypothesis that preventing the caloric deficit with intravenous nutrition would attenuate muscle atrophy and weakness. However, such nutritional interventions failed to prevent severe muscle atrophy. Recent studies pinpoint two potential explanations for the lack of success. First, aggravation of hyperglycemia as catabolic factor by intravenous nutrition may counteract any potential benefit of the artificial feeding. Second, preservation of muscle mass with forced nutrition may come at the expense of suppressed autophagy and compromised muscle quality and function.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

Abbreviations

Atg:

Autophagy-related gene

BNIP3:

Bcl-2/adenovirus E1B nineteen kilodalton-interacting protein-3

ICU:

Intensive care unit

LAMP-2A:

Lysosome-associated membrane protein 2A

LC3:

Microtubule-associated protein light chain-3

mTOR:

Mammalian target of rapamycin

MuRF-1:

Muscle-Ring-Finger-1

PE:

Phosphatidylethanolamine

PI3K:

Phosphatidylinositol-3-kinase

ULK1:

Unc-51-like kinase

VPS:

Vesicular protein sorting

References

  • Apkon A. Cellular physiology of skeletal, cardiac and smooth muscle. In: Boron WF, Boulpaep EL, editors. Medical physiology: a cellular and molecular approach. 1st ed. Philadelphia: Saunders, Elsevier; 2003. p. 230–54.

    Google Scholar 

  • Attaix D, Baracos VE. MAFbx/Atrogin-1 expression is a poor index of muscle proteolysis. Curr Opin Clin Nutr Metab Care. 2010;13:223–4.

    Article  PubMed  Google Scholar 

  • Banduseela VC, Chen YW, Göransson Kultima H, et al. Impaired autophagy, chaperone expression and protein synthesis in response to critical illness interventions in porcine skeletal muscle. Physiol Genomics. 2013;45(12):477–86.

    Google Scholar 

  • Bartoli M, Richard I. Calpains in muscle wasting. Int J Biochem Cell Biol. 2005;37:2115–33.

    Article  CAS  PubMed  Google Scholar 

  • Casaer MP, Mesotten D, Hermans G, et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med. 2011;365:506–17.

    Article  CAS  PubMed  Google Scholar 

  • de Boer MD, Selby A, Atherton P, et al. The temporal responses of protein synthesis, gene expression and cell signalling in human quadriceps muscle and patellar tendon to disuse. J Physiol. 2007;585:241–51.

    Article  PubMed Central  PubMed  Google Scholar 

  • De Jonghe B, Bastuji-Garin S, Durand MC, et al. Respiratory weakness is associated with limb weakness and delayed weaning in critical illness. Crit Care Med. 2007;35:2007–15.

    Article  PubMed  Google Scholar 

  • Debaveye Y, Van den Berghe G. Risks and benefits of nutritional support during critical illness. Annu Rev Nutr. 2006;26:513–38.

    Article  CAS  PubMed  Google Scholar 

  • Derde S, Vanhorebeek I, Ververs EJ, et al. Increasing intravenous glucose load in the presence of normoglycemia: effect on outcome and metabolism in critically ill rabbits. Crit Care Med. 2010;38:602–11.

    Article  CAS  PubMed  Google Scholar 

  • Derde S, Hermans G, Derese I, et al. Muscle atrophy and preferential loss of myosin in prolonged critically ill patients. Crit Care Med. 2012a;40:79–89.

    Article  PubMed  Google Scholar 

  • Derde S, Vanhorebeek I, Güiza F, et al. Early parenteral nutrition evokes a phenotype of autophagy deficiency in liver and skeletal muscle of critically ill rabbits. Endocrinology. 2012b;153:2267–76.

    Article  CAS  PubMed  Google Scholar 

  • Deval C, Mordier S, Obled C, et al. Identification of cathepsin L as a differentially expressed message associated with skeletal muscle wasting. Biochem J. 2001;360:143–50.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Doig GS, Simpson F, Sweetman EA, et al. Early parenteral nutrition in critically ill patients with short-term relative contraindications to early enteral nutrition: a randomized controlled trial. JAMA. 2013;309:2130–8.

    Article  CAS  PubMed  Google Scholar 

  • Du J, Wang X, Miereles C, et al. Activation of caspase-3 is an initial step triggering accelerated muscle proteolysis in catabolic conditions. J Clin Invest. 2004;113:115–23.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Eskelinen EL, Saftig P. Autophagy: a lysosomal degradation pathway with a central role in health and disease. Biochim Biophys Acta. 2009;1793:664–73.

    Article  CAS  PubMed  Google Scholar 

  • Fareed MU, Evenson AR, Wei W, et al. Treatment of rats with calpain inhibitors prevents sepsis-induced muscle proteolysis independent of atrogin-1/MAFbx and MuRF1 expression. Am J Physiol Regul Integr Comp Physiol. 2006;290:R1589–97.

    Article  CAS  PubMed  Google Scholar 

  • Flakoll PJ, Hill JO, Abumrad NN. Acute hyperglycemia enhances proteolysis in normal man. Am J Physiol. 1993;265:E715–21.

    CAS  PubMed  Google Scholar 

  • Glickman MH, Ciechanover A. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev. 2002;82:373–428.

    CAS  PubMed  Google Scholar 

  • Glover EI, Phillips SM. Resistance exercise and appropriate nutrition to counteract muscle wasting and promote muscle hypertrophy. Curr Opin Clin Nutr Metab Care. 2010;13:630–4.

    Article  PubMed  Google Scholar 

  • Gore DC, Chinkes DL, Hart DW, Wolf SE, Herndon DN, Sanford AP. Hyperglycemia exacerbates muscle protein catabolism in burn-injured patients. Crit Care Med. 2002;30:2438–42.

    Article  CAS  PubMed  Google Scholar 

  • Grau T, Bonet A. Caloric intake and liver dysfunction in critically ill patients. Curr Opin Clin Nutr Metab Care. 2009;12:175–9.

    Article  PubMed  Google Scholar 

  • Grumati P, Coletto L, Sabatelli P, et al. Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration. Nat Med. 2010;16:1313–20.

    Article  CAS  PubMed  Google Scholar 

  • Hasselgren PO, Fischer JE. Muscle cachexia: current concepts of intracellular mechanisms and molecular regulation. Ann Surg. 2001;233:9–17.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009;43:67–93.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Heidegger CP, Berger MM, Graf S, et al. Optimisation of energy provision with supplemental parenteral nutrition in critically ill patients: a randomised controlled clinical trial. Lancet. 2013;381:385–93.

    Article  PubMed  Google Scholar 

  • Helliwell TR, Wilkinson A, Griffiths RD, et al. Muscle fiber atrophy in critically ill patients is associated with the loss of myosin filaments and the presence of lysosomal enzymes and ubiquitin. Neurophatol Appl Neurobiol. 1998;24:507–17.

    Article  CAS  Google Scholar 

  • Heyland DK, Dhaliwal R, Drover JW, Canadian Critical Care Clinical Practice Guidelines Committee, et al. Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients. JPEN J Parenter Enteral Nutr. 2003;27:355–73.

    Article  PubMed  Google Scholar 

  • Heyland D, Muscedere J, Wishmeyer PE, et al. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med. 2013;368:1489–97.

    Article  CAS  PubMed  Google Scholar 

  • Hosokawa S, Koseki H, Nagashima M, et al. Title efficacy of phosphodiesterase 5 inhibitor on distant burn-induced muscle autophagy, microcirculation, and survival rate. Am J Physiol Endocrinol Metab. 2013;304:E922–33.

    Article  CAS  PubMed  Google Scholar 

  • Hussain SN, Mofarrahi M, Sigala I, et al. Mechanical ventilation-induced diaphragm disuse in humans triggers autophagy. Am J Respir Crit Care Med. 2010;182:1377–86.

    Article  CAS  PubMed  Google Scholar 

  • Kelly DA. Intestinal failure-associated liver disease: what do we know today? Gastroenterology. 2006;130:S70–7.

    Article  CAS  PubMed  Google Scholar 

  • Kisselev AF, Akopian TN, Castillo V, Goldberg AL. Proteasome active sites allosterically regulate each other, suggesting a cyclical bite-chew mechanism for protein breakdown. Mol Cell. 1999;4:395–402.

    Article  CAS  PubMed  Google Scholar 

  • Klaude M, Fredriksson K, Tjäder I, et al. Proteasome proteolytic activity in skeletal muscle is increased in patients with sepsis. Clin Sci (Lond). 2007;112:499–506.

    Article  CAS  Google Scholar 

  • Komatsu M, Ichimura Y. Physiological significance of selective degradation of p62 by autophagy. FEBS Lett. 2010;584:1374–8.

    Article  CAS  PubMed  Google Scholar 

  • Komatsu M, Waguri S, Ueno T, et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol. 2005;169:425–34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Komatsu M, Waguri S, Koike M, et al. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell. 2007;131:1149–63.

    Article  CAS  PubMed  Google Scholar 

  • Kroemer G, Mariño G, Levine B. Autophagy and the integrated stress response. Mol Cell. 2010;40:280–93.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lang CH, Huber D, Frost RA. Burn-induced increase in atrogin-1 and MuRF-1 in skeletal muscle is glucocorticoid independent but downregulated by IGF-I. Am J Physiol Regul Integr Comp Physiol. 2007;292:R328–36.

    Article  CAS  PubMed  Google Scholar 

  • Larsson L. Acute quadriplegic myopathy: an acquired “myosinopathy”. In: Laing N, editor. The sarcomere and skeletal muscle diseases. Austin: Landes Bioscience; 2008. p. 92–8.

    Chapter  Google Scholar 

  • Larsson L, Li X, Edström L, Eriksson LI, et al. Acute quadriplegia and loss of muscle myosin in patients treated with nondepolarizing neuromuscular blocking agents and corticosteroids: mechanisms at the cellular and molecular levels. Crit Care Med. 2000;28:34–45.

    Article  CAS  PubMed  Google Scholar 

  • Latronico N, Bolton CF. Critical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis. Lancet Neurol. 2011;10:931–41.

    Article  PubMed  Google Scholar 

  • Latronico N, Guarneri B. Critical illness myopathy and neuropathy. Minerva Anestesiol. 2008;74:319–23.

    CAS  PubMed  Google Scholar 

  • Lecker SH. Ubiquitin-protein ligases in muscle wasting: multiple parallel pathways? Curr Opin Clin Nutr Metab Care. 2003;6:271–5.

    CAS  PubMed  Google Scholar 

  • Man WDC, Kemp P, Moxham J, Polkey MI. Skeletal muscle dysfunction in COPD: clinical and laboratory observations. Clin Sci. 2009;117:251–64.

    Article  CAS  PubMed  Google Scholar 

  • Mansoor O, Beaufrere B, Boirie Y, et al. Increased mRNA levels for components of the lysosomal, Ca2+-activated, and ATP-ubiquitin-dependent proteolytic pathways in skeletal muscle from head trauma patients. Proc Natl Acad Sci U S A. 1996;93:2714–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Martindale RG, McClave SA, Vanek VW, American College of Critical Care Medicine, A.S.P.E.N. Board of Directors, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine and American Society for Parenteral and Enteral Nutrition: Executive Summary. Crit Care Med. 2009;37:1757–61.

    Article  PubMed  Google Scholar 

  • Martinet W, Agostinis P, Vanhoecke B, et al. Autophagy in disease: a double-edged sword with therapeutic potential. Clin Sci. 2009;116:697–712.

    Article  CAS  PubMed  Google Scholar 

  • Masiero E, Agatea L, Mammucari C, et al. Autophagy is required to maintain muscle mass. Cell Metab. 2009;10:507–15.

    Article  CAS  PubMed  Google Scholar 

  • Mason RW. Lysosomal metabolism of proteins. Subcell Biochem. 1996;27:159–90.

    Article  CAS  PubMed  Google Scholar 

  • McCowen KC, Malhotra A, Bistrian BR. Stress-induced hyperglycemia. Crit Care Clin. 2001;17:107–24.

    Article  CAS  PubMed  Google Scholar 

  • Mitch WE, Goldberg AL. Mechanisms of muscle wasting. The role of the ubiquitin-proteasome pathway. N Engl J Med. 1996;335:1897–905.

    Article  CAS  PubMed  Google Scholar 

  • Ochala J, Larsson L. Effects of a preferential myosin loss on Ca2+ activation of force generation in single human skeletal muscle fibres. Exp Physiol. 2008;93:486–95.

    Article  CAS  PubMed  Google Scholar 

  • Quy PN, Kuma A, Pierre P, Mizushima N. Proteasome-dependent activation of mammalian target of rapamycin complex 1 (mTORC1) is essential for autophagy suppression and muscle remodeling following denervation. J Biol Chem. 2013;288:1125–34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Reid MB, Moylan JS. Beyond atrophy: redox mechanisms of muscle dysfunction in chronic inflammatory disease. J Physiol. 2011;589:2171–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Reid CL, Campbell IT, Little RA. Muscle wasting and energy balance in critical illness. Clin Nutr. 2004;23:273–80.

    Article  PubMed  Google Scholar 

  • Rice TW, Wheeler AP, Thompson BT, et al. Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA. 2012;307:795–803.

    Article  PubMed  Google Scholar 

  • Sachdeva UM, Thompson CB. Diurnal rhythms of autophagy: implications for cell biology and human disease. Autophagy. 2008;4:581–9.

    Article  CAS  PubMed  Google Scholar 

  • Schakman O, Dehoux M, Bouchuari S, et al. Role of IGF-I and the TNFa/NFkB pathway in the induction of muscle atrogenes by acute inflammation. Am J Physiol Endocrinol Metab. 2012;303:E729–39.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Shaw JH, Holdaway CM. Protein-sparing effect of substrate infusion in surgical patients is governed by the clinical state, and not by the individual substrate infused. JPEN J Parenter Enteral Nutr. 1988;12:433–40.

    Article  CAS  PubMed  Google Scholar 

  • Singer P, Berger MM, Van den Berghe G, ESPEN, et al. ESPEN guidelines on parenteral nutrition: intensive care. Clin Nutr. 2009;28:387–400.

    Article  PubMed  Google Scholar 

  • Singh R, Cuervo AM. Autophagy in the cellular energetic balance. Cell Metab. 2011;13:495–504.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Streat SJ, Beddoe AH, Hill GL. Aggressive nutritional support does not prevent protein loss despite fat gain in septic intensive care patients. J Trauma. 1987;27:262–6.

    Article  CAS  PubMed  Google Scholar 

  • Terman A. Catabolic insufficiency and aging. Ann N Y Acad Sci. 2006;1067:27–36.

    Article  CAS  PubMed  Google Scholar 

  • Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345:1359–67.

    Article  PubMed  Google Scholar 

  • Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354:449–61.

    Article  PubMed  Google Scholar 

  • Vanhorebeek I, Van den Berghe G. Hormonal and metabolic strategies to attenuate catabolism in critically ill patients. Curr Opin Pharmacol. 2004;4:621–8.

    Article  CAS  PubMed  Google Scholar 

  • Vanhorebeek I, Gunst J, Derde S, et al. Insufficient activation of autophagy allows cellular damage to accumulate in critically ill patients. J Clin Endocrinol Metab. 2011;96:E633–45.

    Article  CAS  PubMed  Google Scholar 

  • Vlasselaers D, Milants I, Desmet L, et al. Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study. Lancet. 2009;373:547–56.

    Article  CAS  PubMed  Google Scholar 

  • Voisin L, Breuillé D, Combaret L, et al. Muscle wasting in a rat model of long-lasting sepsis results from the activation of lysosomal, Ca2+-activated, and ubiquitin-proteasome proteolytic pathways. J Clin Invest. 1996;97:1610–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Williams AB, Decourten-Myers GM, Fischer JE, et al. Sepsis stimulates release of myofilaments in skeletal muscle by a calcium-dependent mechanism. FASEB J. 1999;13:1435–43.

    CAS  PubMed  Google Scholar 

  • Wilmore DW. Catabolic illness. Strategies for enhancing recovery. N Engl J Med. 1991;325:695–702.

    Article  CAS  PubMed  Google Scholar 

  • Wolfe RR. The underappreciated role of muscle in health and disease. Am J Clin Nutr. 2006;84:475–82.

    CAS  PubMed  Google Scholar 

  • Yang Z, Klionsky DJ. Eaten alive: a history of macroautophagy. Nat Cell Biol. 2010;12:814–22.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Youle RJ, Narendra DP. Mechanisms of mitophagy. Nat Rev Mol Cell Biol. 2011;12:9–14.

    Article  CAS  PubMed  Google Scholar 

  • Zhao J, Brault JJ, Schild A, et al. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab. 2007;6:472–83.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Intensive Care Medicine, Division Cellular and Molecular Medicine, KU Leuven, B-3000, Leuven, Belgium

    Ilse Vanhorebeek

Authors
  1. Ilse Vanhorebeek
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ilse Vanhorebeek .

Editor information

Editors and Affiliations

  1. Department of Nutrition, King's College London, London, United Kingdom

    Rajkumar Rajendram

  2. School of Medicine, King's College London, London, United Kingdom

    Victor R. Preedy

  3. Department of Biomedical Sciences, University of Westminster, London, United Kingdom

    Vinood B. Patel

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this entry

Cite this entry

Vanhorebeek, I. (2014). Muscle Weakness, Molecular Mechanism, and Nutrition During Critical Illness. In: Rajendram, R., Preedy, V., Patel, V. (eds) Diet and Nutrition in Critical Care. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8503-2_29-1

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-8503-2_29-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, New York, NY

  • Online ISBN: 978-1-4614-8503-2

  • eBook Packages: Springer Reference MedicineReference Module Medicine

Publish with us

Policies and ethics

Search

Navigation