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Hypercatabolic Syndrome: Molecular Basis and Effects ofNutritional Supplements with Amino Acids

Evasio Pasini, MDa,*, Roberto Aquilani, MDb, Francesco S. Dioguardi, MDc,Giuseppe D’Antona, MD, PhDd, Mihai Gheorghiade, MDe, and

Heinrich Taegtmeyer, MD, DPhilf

Hypercatabolic syndrome (HS) is a biochemical state characterized by increased circu-lating catabolic hormones (eg, cortisol, catecholamines) and inflammatory cytokines (eg,tumor necrosis factors, interleukin–1�), and decreased anabolic insulin effects withconsequent insulin resistance. The most important metabolic consequence of HS is theskeletal and cardiac muscle protein breakdown that releases amino acids (AAs), which inturn supports indispensable body energy requirements but also reduces skeletal andcardiac physiologic and metabolic functions. HS occurs in many diseases such as diabetesmellitus, chronic heart failure, chronic obstructive pulmonary disease, renal and liverfailure, trauma, sepsis, and senescence. All of these conditions have predominant cata-bolic molecules with significant muscular wasting and metabolic impairment. Macronu-trients such as AA supplements, taken together with conventional therapy, may maintainmuscular protein metabolism and cell functions. © 2008 Elsevier Inc. All rights re-

served. (Am J Cardiol 2008;101[suppl]:11E–15E)

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s pointed out by Anker and associates and others,1,2 hyper-atabolic syndrome (HS) is a biochemical state characterizedy increased circulating catabolic molecules such as hormoneseg, cortisol, glucagons, catecholamines) and inflammatoryytokines (e.g., tumor necrosis factor [TNF]–�, interleukinIL]–1�, IL-6), and decreased anabolic insulin effects withubsequent insulin resistance and muscular wasting.

he Molecular Basis of Hypercatabolic Syndrome

n normal cardiac and skeletal muscles, the continual turn-ver of proteins is a basic process of cell life. Data show thatn healthy humans, approximately 250–350 g of proteinsre degraded in the muscles each day. Although some of themino acids (AAs) produced are reused from cells to syn-hesize cytoplasmic and mitochondrial new proteins or to

aFoundation “Salvatore Maugeri,” IRCCS, Scientific Institute of Lu-ezzane, Brescia, Italy; bFoundation “Salvatore Maugeri,” IRCCS, Ser-

ice of Metabolic and Nutritional Pathophysiology, Medical Center ofontescano, Montescano, Pavia, Italy; cDepartment of Internal Medicine,niversity of Milan, Milan, Italy; dDepartment of Experimental Medicine,uman Physiology Unit, University of Pavia, Pavia, Italy; eDivision ofardiology, Department of Medicine, Feinberg School of Medicine, North-estern University, Chicago, USA; and fDivision of Cardiology, Depart-ent of Internal Medicine, University of Texas Medical School of Hous-

on, Houston, Texas, USA.Statement of author disclosure: Please see the Author Disclosures

ection at the end of this article.*Address for reprints: Evasio Pasini, MD, Foundation “Salvatore

augeri,” IRCCS, Medical Center of Lumezzane, via Mazzini 129, 25066umezzane, Brescia, Italy.

iE-mail address: evpasini@libero.it.

002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2008.02.074

roduce energetic intermediates, a large quantity of AAs areeleased into the blood to maintain the blood pool of AAsFigure 1). Thus, the balance between protein synthesis andreakdown determines the overall cell protein content andetabolism. The balance of protein production or degrada-

ion is regulated by the balance of catabolic and anabolictimuli (Figure 1). The increase of catabolic hormonesnd/or molecules (eg, catecholamines, cortisol, glucagon,NF-�) and the reduction of anabolic hormone (eg, insulin)reate an HS that has various metabolic consequences, in-luding reduced cytoplasmic and mitochondrial cell pro-eins synthesis and impaired cell functions and energeticetabolism. Indeed, AAs are used not only for cellular

rotein replacement and/or cellular energy production butlso for the metabolism of the human body (Figure 2).2–5

he AAs released from skeletal and cardiac muscle are usedn the liver to produce glucose by gluconeogenesis, becauselucose is essential for maintenance of the glucose-depen-ent metabolism of fundamental structures such as the brainnd erythrocytes (Figures 1 and 2). Consequently, the mus-le is not merely an organ restricted to movement or con-raction; it also has an important role in maintaining theeneral metabolism of the human body. In addition, muscleass is approximately 45% of the dry weight of a healthy

erson, and most receptors for insulin, cortisol, and gluca-on are located in the muscle.5–8

hen Does Hypercatabolic Syndrome Occur?

ecent studies have identified HS with muscular wastingnd cellular energy impairment in chronic diseases, includ-

ng diabetes mellitus, chronic heart failure (CHF), chronic

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12E The American Journal of Cardiology (www.AJConline.org) Vol 101 (11A) June 2, 2008

bstructive pulmonary disease (COPD), and renal and liverailure, as well as in infectious diseases and sepsis. Inter-stingly, HS is also present in healthy elderly individu-ls.1,2,9,10

ral Amino Acids: A Possible Therapeutic Approacho Counteracting Hypercatabolic Syndrome

he availability of AAs is a key factor in maintaining bothellular and general metabolism and muscle protein synthe-is in mammals. Preliminary data suggest that exogenousral AA supplements, administered with traditional therapy,ounteract muscular wasting and cellular energy reduction,nd may improve cardiac function and muscle performance,hereby enhancing the patient’s quality of life.11–18

In healthy subjects, AAs in the diet are absorbed afterrotein digestion. However, the pancreas uses largemounts of AAs to produce digestive enzymes.7 In HS, thefficiency of the pancreas and mesenteric circulation may berogressively reduced. These conditions lead to impairedA digestion and absorption and, consequently, to reduced

igure 1. In healthy humans, proteins are degraded in the muscles every do synthesize cytoplasmic and mitochondrial new proteins or to produceaintain the blood pool of AAs. The balance of protein production or deg

nsulin-like growth factor–�.

A plasma patterns that may therefore be insufficient to p

aintain the protein synthesis and energetic needs of pa-ients with HS.

In contrast, individual AAs in nutritional supplementsre not digested. They are rapidly absorbed and thereforemmediately available in the bloodstream and transportednto the cells, where they stimulate cellular protein synthesisnd mitochondrial biogenesis as shown by preliminary re-ults.2,4,19

hy Are Orally Administered Amino Acids Active inypercatabolic Syndrome?

igh physiologic concentrations of AAs activate importantrocesses of both cytosolic and mitochondrial protein syn-hesis.4 Data have shown that AAs influence fundamentalnzymes involved in cell protein synthesis such as p706-kinase (S6K1) and eukaryotic initiation factor elF4Fegulation. Interestingly, AAs act through a mammalianarget of rapamycin (mTOR)–mediated mechanism that isn insulin-independent pathway. mTOR is an ubiquitous

ough some of the amino acids (AAs ) produced are reused from the cellstic intermediates, a large quantity of AAs are released into the blood ton is regulated by the balance of catabolic and anabolic stimuli. IGF-� �

ay. Althenergeradatio

rotein kinase that integrates signals from hormones and

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13EPasini et al/Nutrients and Hypercatabolic States

utrients; it stimulates both protein and DNA synthesis andegulates cell growth, proliferation, and survival.20

Preliminary data also suggest that oral supplements of apecific mixture of AAs increase muscular number andolume of mitochondria. This point is particularly importantor patients with chronic diseases such as diabetes, senes-ence, and CHF, where impaired mitochondrial activitiesnd disarrangement of energy metabolism are present in theuscles.21,22

Furthermore, recent results suggest that prolonged oralupplementation with a specific AA mixture upregulatesuscular glucose transporter-4 expression in diabetic ratsithout interfering with intracellular insulin signaling. On

he other hand, clinical data show that oral AA supplemen-ation reduces blood glucose and improves both insulinesistance and cardiac mechanical functions in patients withiabetes.14–17,23,24 It is important to note that AAs can re-ctivate glucose cell metabolism in an insulin-independentanner.25,26 These results suggest the existence in the mus-

les of archaic metabolic pathways that are (1) insulinndependent and (2) stimulated by nutrients such as AAs.

igure 2. The increase of catabolic hormones and/or molecules (eg, catechoormone (eg, insulin) create a hypercatabolic syndrome that reduces cytonergetic metabolism. Amino acids (AAs) are used not only for cellular prokeletal and cardiac muscle and used to produce glucose or other metabolictructures. IGF � insulin-like growth factor.

hese pathways are silent under normal conditions, but they i

re stimulated by oral AA supplements when the insulin-ependent pathway is impaired.20 Therefore, these insulin-ndependent pathways are important for overcoming cellu-ar damage induced by HS that compromises celletabolism.

onclusion

hronic diseases, such as diabetes, heart failure, and senes-ence, share the common denominator of HS with insulinesistance. HS is characterized by increased hormonal cat-bolic stimuli that cause muscle protein breakdown andonsequent cell release of AAs, muscular wasting, and al-ered energy production. Basic laboratory and clinical evi-ence shows that oral administration of AAs stimulatesytosolic muscle protein synthesis, mitochondrial biogene-is, and glucose intracellular transport and use. These mech-nisms may help to maintain skeletal and cardiac muscletructures and energy content; importantly, these AA activ-ties use an insulin-independent pathway. Increased protein

, cortisol, glucagon, tumor necrosis factor–�) and the reduction of anabolicand mitochondrial cell proteins synthesis and impairs cell functions and

lacement and/or cellular energy production but they also are released fromediates that are essential to maintain the metabolism of fundamental body

laminesplasmictein repinterm

ntake with meals does not increase protein synthesis, be-

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14E The American Journal of Cardiology (www.AJConline.org) Vol 101 (11A) June 2, 2008

ause the meal must be digested and absorbed and, often, asn the case of chronic diseases, the exocrine pancreas andesenteric circulation are impaired. Individual AAs intro-

uced by nutritional supplementation are not digested, butre rapidly absorbed with massive blood increases and eas-ly transported into cells, where AAs maintain myocytetructure and metabolism. As a result, nutritional supple-entation with AAs counteracts catabolic stimuli present in

hronic diseases by stimulating muscle metabolic and struc-ural changes that prevent skeletal and cardiac muscularasting and impaired energetic metabolism with conse-uent functional damage.

Supplementation with oral AA mixtures, taken togetherith conventional therapies, potentially may be used in

hronic diseases such as diabetes and CHF or in physiologiconditions such as senescence that are characterized byatabolic stimuli with impaired protein metabolism and,onsequently, muscular wasting and energy impairment.

cknowledgment

e thank medical writer Dr. Robert Coates (Centro Lin-uistico, Bocconi University, Milan, Italy) for his linguisticevision.

uthor Disclosures

he authors who contributed to this article have disclosedhe following industry relationships:

Evasio Pasini, MD, has no financial arrangement orffiliation with a corporate organization or a manufacturerf a product discussed in this article.

Roberto Aquilani, MD, has no financial arrangement orffiliation with a corporate organization or a manufacturerf a product discussed in this article.

Francesco S. Dioguardi, MD, serves as a consultant torofessional Dietetics s.r.l.

Giuseppe D’Antona, MD, PhD, has no financial ar-angement or affiliation with a corporate organization or aanufacturer of a product discussed in this article.Mihai Gheorghiade, MD, serves as a consultant to

ebbio Pharm, ErreKappa Euroterapici, GlaxoSmithKline,edtronic, Inc., and PDL BioPharma; has received re-

earch/grant support from Merck & Co., Inc., the Nationalnstitutes of Health (NIH), Otsuka Pharmaceutical Co.,CIOS Inc., and Sigma-Tau Pharmaceuticals; and has re-eived honoraria from Abbott Laboratories, AstraZenecaharmaceuticals, GlaxoSmithKline, Medtronic, Inc., Ot-uka Pharmaceutical Co., PDL BioPharma, SCIOS Inc., andigma-Tau Pharmaceuticals.

Heinrich Taegtmeyer, MD, DPhil, has no financialrrangement or affiliation with a corporate organization or a

anufacturer of a product discussed in this article.

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