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Contents lists available at ScienceDirect

Ageing Research Reviews journal homepage: www.elsevier.com/locate/arr

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Review

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Sarcopenia – The search for emerging biomarkers

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Alexander Kalinkovich, Gregory Livshits ∗ Human Population Biology Research Unit, Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

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Article history: Received 21 March 2015 Received in revised form 6 May 2015 Accepted 6 May 2015 Available online xxx

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Keywords: Sarcopenia Biomarker Muscle mass deterioration Neuromuscular junction Inflamm-aging

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Contents

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Sarcopenia, an age-related decline in skeletal muscle mass and function, dramatically affects the life quality of elder people. In view of increasing life expectancy, sarcopenia renders a heavy burden on the health care system. However, although there is a consensus that sarcopenia is a multifactorial syndrome, its etiology, underlying mechanisms, and even definition remain poorly delineated, thus, preventing development of a precise treatment strategy. The main aim of our review is to critically analyze potential sarcopenia biomarkers in light of the molecular mechanisms of their involvement in sarcopenia pathogenesis. Normal muscle mass and function maintenance are proposed to be dependent on the dynamic balance between the positive regulators of muscle growth such as bone morphogenetic proteins (BMPs), brain-derived neurotrophic factor (BDNF), follistatin (FST) and irisin, and negative regulators including TGF␤, myostatin, activins A and B, and growth and differentiation factor-15 (GDF-15). We hypothesize that the shift in this balance to muscle growth inhibitors, along with increased expression of the C- terminal agrin fragment (CAF) associated with age-dependent neuromuscular junction (NMJ) dysfunction, as well as skeletal muscle-specific troponin T (sTnT), a key component of contractile machinery, is a main mechanism underlying sarcopenia pathogenesis. Thus, this review proposes and emphasizes that these molecules are the emerging sarcopenia biomarkers. © 2015 Elsevier B.V. All rights reserved.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Definition of sarcopenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sarcopenia biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. IL-6 as a prototype of sarcopenia biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Negative regulators of muscle growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Myostatin and TGF␤ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Activins A and B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3. GDF-15 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Positive regulators of muscle growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.1. FST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.2. BMPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.3. Irisin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: Ach, acetylcholine; ActR, activin type receptor; ALK, activin-like kinase; BDNF, brain-derived neurotrophic factor; BMD, bone mineral density; BMPs, bone morphogenic proteins; CAF, terminal agrin fragment; CNS, central nervous system; DHPR, dihydropyridine receptor; ECM, extracellular matrix; FNDC5, fibronectin type III domain containing protein 5; FOXO, forkhead box O; FST, follistatin; GDF, growth and differentiation factor; IL, interleukin; LAP, latency associated peptide; LPS, lipopolysaccharide; LRP, lipoprotein receptor-related protein; MIC-1, macrophage inhibitory cytokine 1; mTOR, mammalian target of rapamycin; MuSK, muscle-specific kinase; MyoD, myogenic differentiation factor; p75NTR, p75 neurotrophin receptor; RyR, ryanodine receptor; SMM, skeletal muscular mass SMM; sTnT, skeletal musclespecific troponin T; TAK-1, TGF␤activated kinase 1; TGF␤, transforming growth factor beta; TNF␣, tumor necrosis factor alpha; TnT, tropomyosin-binding subunit troponin T; TrkBR, tropomyosin-related kinase-B receptor. ∗ Corresponding author at: Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel. Tel.: +972 3 640 9494; fax: +972 3 640 8287. E-mail address: [email protected] (G. Livshits). http://dx.doi.org/10.1016/j.arr.2015.05.001 1568-1637/© 2015 Elsevier B.V. All rights reserved.

Please cite this article in press as: Kalinkovich, A., Livshits, G., Sarcopenia – The search for emerging biomarkers. Ageing Res. Rev. (2015), http://dx.doi.org/10.1016/j.arr.2015.05.001

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3.3.4. BDNF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Aging-associated impairment of NMJs CAF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. The muscle contractility regulatory proteins sTnT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction

Lean body mass, in particular, skeletal muscular mass (SMM), represents one of the three major components of body composition, which also includes fat and bone mass. All components are highly 39 important for normal physiology and metabolism, and deviations 40 from normal values, in particular, related to age, are often asso41 ciated with various pathological conditions. The health risks and 42 complications caused by obesity and bone loss, as well as osteo43 porosis are well established, and the implications of age-related 44 SMM loss have recently attracted increasing attention (Berger and 45 Doherty, 2010). 46 Skeletal muscle is the largest organ in the human body and con47 tributes up to 60% of the total body weight in young non-obese 48 adults. After the age of 30, about 0.5–1% of SMM is lost per year, with 49 a dramatic acceleration of the rate of decline after the age of 65 (Kyle 50 et al., 2001; Melton et al., 2006). On average, 5–13% of older persons 51 over 60 have low SMM, with the prevalence increasing to as high as 52 50% in persons over the age of 80 (Morley et al., 2014). Muscle func53 tional capacity (strength and power) also decreases with advancing 54 age, and even to a greater degree than SMM (Newman et al., 2003.) 55 This age- related reduction in SMM and function is referred to as 56 “sarcopenia” (from Greek sarx “flesh” and penia “loss”). It is asso57 ciated with limitations of physical performance in older people, 58 leading to increased risk of falls, fractures, hospitalization, depen59 dency, frailty, profound metabolic consequences, and mortality 60 (Abellan van Kan, 2009; Janssen, 2011; Liu et al., 2014). Moreover, 61 although sarcopenia is generally observed and diagnosed in older 62 adults, it may be present in different clinical settings, including 63 critical illness. Recent data also demonstrated that sarcopenia in 64 an intensive care unit negatively impacts patients’ outcomes and 65 may promote functional disability in the long-term after hospital 66 discharge (Muscaritoli et al., 2013). 67 Sarcopenia has been reported to affect more than 40% of elderly 68 individuals >70 years of age, approximately 50 million people 69 worldwide. Taking into account the increase in life expectancy that 70 has occurred during the last decades, this number is estimated to 71 increase 10-fold in the year 2050 (Hida et al., 2013). However, not 72 all the individuals display the same rate of SMM loss, and consid73 erable variation in SMM exists among individuals of the same age 74 (Fig. 1). An important open question is what are the major factors 75 that cause this variation? It is clear that a variety of intrinsic and 76 extrinsic sources are involved in this situation, including (but not 77 limited to) a mixture of life style as well as genetic and metabolic 78 factors. 79 Currently the contribution of the genetic and familial factors 80 to a variation of SMM is well established, and heritability esti81 mates in studies reach 40% or even higher (Garatachea and Lucia, 82 2013; Korostishevsky et al., 2015; Nabulsi et al., 2013). How83 ever, replicated and confirmed specific genetic polymorphisms are 84 85Q3 rare and are able to explain only a minor part of this variation (Livshits et al., 2012; Rothammer et al., 2014; Urano et al., 2014; 86 Zillikens et al., 2015). As such, no solid evidence currently exists 87 supporting an “unfavorable” genotype associated with accelerated 88 sarcopenia or frailty, or a combination of molecular-genetic factors 89 explaining the significant part of the inter-individual variation in 90 SMM. 91 37 38

Fig. 1. Age dependence of relative skeletal muscle mass (SMM) in a UK sample of female twins. The figure shows significant diminution of the SMM with age in the general human population. The axis X shows the age of the individual in years, the axis Y shows the SMM. The SMM was computed as a ratio of the appendicular (sum of upper and lower limbs) lean mass, in kilograms (assessed by dual-energy X-ray absorptiometry) to a total body fat mass (kg) for each of the individuals examined in our previous study (Korostishevsky et al., 2015). The figure based on a crosssectional study sample of 3953 females with mean age 50 years, but wide range, from 18 to 82 years. By likelihood ratio test, the data well fitted by linear regression line, with highly statistically significant (p < 0.001) inverse correlation, 0.350.

Likewise, although the term “sarcopenia” has become widespread, the criteria for its definition and clinical diagnosis are not yet clear-cut and vary among studies and experts. Nevertheless, there is a consensus that sarcopenia is a multifactorial syndrome (Berardi et al., 2014; Lauretani et al., 2014; Santilli et al., 2014) and correlates include endocrine dysfunction and inflammation (Lang et al., 2010; Malafarina et al., 2012). It also became obvious that beyond the basic action of mechanical contraction, the skeletal muscles are involved in endocrine and metabolic activities such as glucose, glycogen, and lipid metabolism (Pedersen and Febbraio, 2012) and perform certain immunogenic functions (Nielsen and Pedersen, 2008). Muscle-derived cytokines, myokines, such as myostatin, interleukin-6 (IL-6), irisin, and others were shown to exert auto, para- and endocrine actions (Pedersen, 2013). They mediate crosstalk between muscle and other tissues, mainly bone, fat, and liver. Their effects include regulation of systemic inflammation, immune function, energy metabolism, insulin sensitivity, cell growth, myogenesis, osteogenesis, and others (Demontis et al., 2013; Iizuka et al., 2014; Pedersen, 2013; Raschke and Eckel, 2013). In addition, a number of factors related to chronic diseases and aging such as oxidative stress, neurodegeneration, anorexia, insulin resistance, mitochondrial dysfunction, and DNA mutations may accelerate sarcopenia (Biolo et al., 2014; Sakuma et al., 2015). These findings indicate that strategies aimed at diagnosing sarcopenia and counteracting its development and progression have to cover multiple and not yet well-defined factors, thus introducing challenges in searching for sarcopenia biomarkers. To date, although numerous biomarkers have been suggested to be associated with SMM and function, only a few are in fact solely muscle-specific biomarkers. Moreover, correlating their blood

Please cite this article in press as: Kalinkovich, A., Livshits, G., Sarcopenia – The search for emerging biomarkers. Ageing Res. Rev. (2015), http://dx.doi.org/10.1016/j.arr.2015.05.001

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levels to sarcopenia parameters is still a controversial issue (Cesari et al., 2014; Lippi et al., 2014). In searching for potentially reliable sarcopenia biomarkers, we selected several molecules expressed by skeletal muscles and divided them into five clusters (Fig. 2). The rationale underlying this stratification is based on the supposed capability of the members of each cluster to significantly affect different aspects of muscle growth and function, finally leading to sarcopenia. This review was prompted by an analysis of these molecules’ mechanisms of action, their interrelationships in sarcopenia pathogenesis, and their role as emerging sarcopenia biomarkers. There are, of course, a variety of additional mechanisms potentially involved in sarcopenia pathogenesis such as mitochondria dysfunction, autophagy, apoptosis, endocrine factors, nutritional status, and immobility. These additional mechanisms have not been considered in the present paper but they have been comprehensively discussed by others (CruzJentoft et al., 2014; Ilich et al., 2014; Kob et al., 2015; Malafarina et al., 2012; Marzetti et al., 2013; Prado and Heymsfield, 2014; Sakuma et al., 2015).

2. Definition of sarcopenia As mentioned, sarcopenia remains a poorly defined phenomenon, even referring to it as a “describing rather than defining condition” (Alchin, 2014). This perhaps explains a huge variance in the estimates of sarcopenia prevalence, ranging from ≤10% (Dam et al., 2014) to ≥70% (Batsis et al., 2014) in individuals older than 60 years, thus, again emphasizing the urgency in clearly defining the sarcopenia cutoff points. The term sarcopenia was first introduced by Rosenberg (1989), referring exclusively to a decline in muscle mass with aging (2 SD below the young adult mean). However, later, muscle dysfunction has been linked to the definition of sarcopenia, thus making the term “sarcopenia with impaired mobility” more clinically applicable (Morley et al., 2001). In addition, European Working Group on Sarcopenia in Older People (EWGSOP) defined three stages for sarcopenia: presarcopenia (loss of muscle mass), sarcopenia (loss of muscle mass accompanied by either loss of strength or physical performance), and severe sarcopenia (all three aspects are present) (Cruz-Jentoft et al., 2010). More recently, the Foundation for the National Institutes of Health Sarcopenia Project (FNIH) used the data collected from nine international sources of community-dwelling older persons (26,625 participants). They extended the methodological approach to diagnostic criteria of sarcopenia by applying “Classification and Regression Tree Analysis” to epidemiologic and clinical trial data (Cawthon et al., 2014; McLean et al., 2014; Studenski et al., 2014). This is a two-step approach aimed at identifying criteria for clinically relevant low muscle strength (weakness) and low lean mass. Since concerns remain as to the best terminology to embrace the evolving concepts of sarcopenia and age-related muscle dysfunction, the concept of “Skeletal Muscle Function Deficit” (SMFD) has been also introduced (Correa-de-Araujo and Hadley, 2014). It comprises the variety of muscular health-associated conditions that contribute to clinically important mobility impairments. “SMFD” attributable to diminished muscle mass has been termed “sarcopenic SMFD,” whereas impairments in muscle strength or power that contribute to SMFD independent of muscle mass (and even in the presence of normal muscle mass) has been termed “dynapenic SMFD”, and mixed categories could also be defined. The authors believe that the concept of “SMFD”, which covers a variety of contributory etiologies, could provide a framework for developing diagnostic categories being useful for both clinical practice and research.

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Overall, currently the standard diagnosis for sarcopenia includes low muscle mass (estimated by the ratio of appendicular lean mass over the height squared, ≤8.0 kg/ht2 for men and ≤6.0 kg/ht2 for women), accompanied by either low muscle strength (measured by grip strength

Sarcopenia--The search for emerging biomarkers.

Sarcopenia, an age-related decline in skeletal muscle mass and function, dramatically affects the life quality of elder people. In view of increasing ...
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