Abstract
The syndrome of cachexia, i.e., involuntary weight loss in patients with underlying diseases, sarcopenia, i.e., loss of muscle mass due to aging, and general muscle atrophy from disuse and/or prolonged bed rest have received more attention over the last decades. All lead to a higher morbidity and mortality in patients, and therefore, they represent a major socio-economic burden for the society today. This mini-review looks at recent developments in basic research that are relevant to the loss of skeletal muscle. It aims to cover the most significant publication of last 3 years on the causes and effects of muscle wasting, new targets for therapy development, and potential biomarkers for assessing skeletal muscle mass. The targets include the following: (1) E-3 ligases TRIM32, SOCS1, and SOCS3 by involving the elongin BC ubiquitin-ligase, Cbl-b, culling 7, Fbxo40, MG53 (TRIM72), and the mitochondrial Mul1; (2) the kinase MST1; and (3) the G-protein Gαi2. D(3)-creatine has the potential to be used as a novel biomarker that allows to monitor actual change in skeletal muscle mass over time. In conclusion, significant development efforts are being made by academic groups as well as numerous pharmaceutical companies to identify new target and biomarker muscles, as muscle wasting represents a great medical need, but no therapies have been approved in the last decades.
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Kalantar-Zadeh K, Rhee C, Sim JJ, Stenvinkel P, Anker SD, Kovesdy CP. Why cachexia kills: examining the causality of poor outcomes in wasting conditions. J Cachexia Sarcopenia Muscle. 2013;4:89–94.
von Haehling S, Morley JE, Anker SD. From muscle wasting to sarcopenia and myopenia: update 2012. J Cachexia Sarcopenia Muscle. 2012;3:213–7.
von Haehling S, Anker SD. Cachexia vs obesity: where is the real unmet clinical need? J Cachexia Sarcopenia Muscle. 2013;4:245–6.
Farkas J, von Haehling S, Kalantar-Zadeh K, Morley JE, Anker SD, Lainscak M. Cachexia as a major public health problem: frequent, costly, and deadly. J Cachexia Sarcopenia Muscle. 2013;4:173–8.
Evans WJ, Morley JE, Argiles J, Bales C, Baracos V, Guttridge D, et al. Cachexia: a new definition. Clin Nutr. 2008;27:793–9.
von Haehling S, Anker SD. Cachexia as a major underestimated and unmet medical need: facts and numbers. J Cachexia Sarcopenia Muscle. 2010;1:1–5.
von Haehling S, Morley JE, Anker SD. An overview of sarcopenia: facts and numbers on prevalence and clinical impact. J Cachexia Sarcopenia Muscle. 2010;1:129–33.
Iannuzzi-Sucich M, Prestwood KM, Kenny AM. Prevalence of sarcopenia and predictors of skeletal muscle mass in healthy, older men and women. J Gerontol A Biol Sci Med Sci. 2002;57:M772–7.
Brooks NE, Myburgh KH. Skeletal muscle wasting with disuse atrophy is multi-dimensional: the response and interaction of myonuclei, satellite cells and signaling pathways. Front Physiol. 2014;5:99.
Marzetti E, Calvani R, Cesari M, Buford TW, Lorenzi M, Behnke BJ, et al. Mitochondrial dysfunction and sarcopenia of aging: from signaling pathways to clinical trials. Int J Biochem Cell Biol. 2013;45:2288–301.
Haran PH, Rivas DA, Fielding RA. Role and potential mechanisms of anabolic resistance in sarcopenia. J Cachexia Sarcopenia Muscle. 2012;3:157–62.
Abstracts of the 7th cachexia conference, Japan, december 9-11, 2013. J Cachexia Sarcopenia Muscle. 2013;4:295-343.
Abstracts of the 7th cachexia conference, kobe/osaka, Japan, december 9-11, 2013 (part 2). J Cachexia Sarcopenia Muscle. 2014;5:35-78.
Vaughan VC, Martin P, Lewandowski PA. Cancer cachexia: impact, mechanisms and emerging treatments. J Cachexia Sarcopenia Muscle. 2013;4:95–109.
Trobec K, von Haehling S, Anker SD, Lainscak M. Growth hormone, insulin-like growth factor 1, and insulin signaling-a pharmacological target in body wasting and cachexia. J Cachexia Sarcopenia Muscle. 2011;2:191–200.
Burney BO, Hayes TG, Smiechowska J, Cardwell G, Papusha V, Bhargava P, et al. Low testosterone levels and increased inflammatory markers in patients with cancer and relationship with cachexia. J Clin Endocrinol Metab. 2012;97:E700–9.
Busquets S, Toledo M, Marmonti E, Orpi M, Capdevila E, Betancourt A, et al. Formoterol treatment downregulates the myostatin system in skeletal muscle of cachectic tumour-bearing rats. Oncol Lett. 2012;3:185–9.
Akamizu T, Kangawa K. Ghrelin for cachexia. J Cachexia Sarcopenia Muscle. 2010;1:169–76.
Schiaffino S, Mammucari C. Regulation of skeletal muscle growth by the IGF1-Akt/PKB pathway: insights from genetic models. Skelet Muscle. 2011;1:4.
Burney BO, Garcia JM. Hypogonadism in male cancer patients. J Cachexia Sarcopenia Muscle. 2012;3:149–55.
Dalton JT, Barnette KG, Bohl CE, Hancock ML, Rodriguez D, Dodson ST, et al. The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial. J Cachexia Sarcopenia Muscle. 2011;2:153–61.
Springer J, Tschirner A, Haghikia A, von Haehling S, Lal H, Grzesiak A, et al. Prevention of liver cancer cachexia-induced cardiac wasting and heart failure. Eur Heart J. 2014;35:932–41.
Pedroso FE, Spalding PB, Cheung MC, Yang R, Gutierrez JC, Bonetto A, et al. Inflammation, organomegaly, and muscle wasting despite hyperphagia in a mouse model of burn cachexia. J Cachexia Sarcopenia Muscle. 2012;3:199–211.
Puppa MJ, White JP, Velazquez KT, Baltgalvis KA, Sato S, Baynes JW, et al. The effect of exercise on IL-6-induced cachexia in the Apc (Min/+) mouse. J Cachexia Sarcopenia Muscle. 2012;3:117–37.
Rezk BM, Yoshida T, Semprun-Prieto L, Higashi Y, Sukhanov S, Delafontaine P. Angiotensin II infusion induces marked diaphragmatic skeletal muscle atrophy. PLoS ONE. 2012;7:e30276.
Elkina Y, Palus S, Tschirner A, Hartmann K, von Haehling S, Doehner W, et al. Tandospirone reduces wasting and improves cardiac function in experimental cancer cachexia. Int J Cardiol. 2013;170:160–6.
Olde Engberink RH, Knippels MC, Pijpers E. Hypomanic episode as a first presentation of a large B-cell lymphoma. Jpn J Clin Oncol. 2013;43:318–20.
Elkina Y, von Haehling S, Anker SD, Springer J. The role of myostatin in muscle wasting: an overview. J Cachexia Sarcopenia Muscle. 2011;2:143–51.
Egerman MA, Glass DJ. Signaling pathways controlling skeletal muscle mass. Crit Rev Biochem Mol Biol. 2014;49:59–68.
Zhou X, Wang JL, Lu J, Song Y, Kwak KS, Jiao Q, et al. Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell. 2010;142:531–43.
Busquets S, Toledo M, Orpi M, Massa D, Porta M, Capdevila E, et al. Myostatin blockage using actRIIB antagonism in mice bearing the Lewis lung carcinoma results in the improvement of muscle wasting and physical performance. J Cachexia Sarcopenia Muscle. 2012;3:37–43.
De Larichaudy J, Zufferli A, Serra F, Isidori AM, Naro F, Dessalle K, et al. TNF-alpha- and tumor-induced skeletal muscle atrophy involves sphingolipid metabolism. Skelet Muscle. 2012;2:2.
Shimizu N, Yoshikawa N, Ito N, Maruyama T, Suzuki Y, Takeda S, et al. Crosstalk between glucocorticoid receptor and nutritional sensor mTOR in skeletal muscle. Cell Metab. 2011;13:170–82.
Der-Torossian H, Wysong A, Shadfar S, Willis MS, McDunn J, Couch ME. Metabolic derangements in the gastrocnemius and the effect of compound A therapy in a murine model of cancer cachexia. J Cachex Sarcopenia Muscle. 2013;4:145–55.
Sakuma K, Yamaguchi A. Sarcopenia and cachexia: the adaptations of negative regulators of skeletal muscle mass. J Cachexia Sarcopenia Muscle. 2012;3:77–94.
Trendelenburg AU, Meyer A, Jacobi C, Feige JN, Glass DJ. TAK-1/p38/nNFkappaB signaling inhibits myoblast differentiation by increasing levels of activin A. Skelet Muscle. 2012;2:3.
Glass DJ. Signaling pathways perturbing muscle mass. Curr Opin Clin Nutr Metab Care. 2010;13:225–9.
Lagirand-Cantaloube J, Offner N, Csibi A, Leibovitch MP, Batonnet-Pichon S, Tintignac LA, et al. The initiation factor eIF3-f is a major target for atrogin1/MAFbx function in skeletal muscle atrophy. EMBO J. 2008;27:1266–76.
Lagirand-Cantaloube J, Cornille K, Csibi A, Batonnet-Pichon S, Leibovitch MP, Leibovitch SA. Inhibition of atrogin-1/MAFbx mediated MyoD proteolysis prevents skeletal muscle atrophy in vivo. PLoS ONE. 2009;4:e4973.
Cohen S, Brault JJ, Gygi SP, Glass DJ, Valenzuela DM, Gartner C, et al. During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1-dependent ubiquitylation. J Cell Biol. 2009;185:1083–95.
Cohen S, Zhai B, Gygi SP, Goldberg AL. Ubiquitylation by Trim32 causes coupled loss of desmin, Z-bands, and thin filaments in muscle atrophy. J Cell Biol. 2012;198:575–89.
An CI, Ganio E, Hagiwara N. Trip12, a HECT domain E3 ubiquitin ligase, targets Sox6 for proteasomal degradation and affects fiber type-specific gene expression in muscle cells. Skelet Muscle. 2013;3:11.
Roberts BM, Ahn B, Smuder AJ, Al-Rajhi M, Gill LC, Beharry AW, et al. Diaphragm and ventilatory dysfunction during cancer cachexia. FASEB J. 2013;27:2600–10.
Rui L, Yuan M, Frantz D, Shoelson S, White MF. SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J Biol Chem. 2002;277:42394–8.
Nakao R, Hirasaka K, Goto J, Ishidoh K, Yamada C, Ohno A, et al. Ubiquitin ligase Cbl-b is a negative regulator for insulin-like growth factor 1 signaling during muscle atrophy caused by unloading. Mol Cell Biol. 2009;29:4798–811.
Xu X, Sarikas A, Dias-Santagata DC, Dolios G, Lafontant PJ, Tsai SC, et al. The CUL7 E3 ubiquitin ligase targets insulin receptor substrate 1 for ubiquitin-dependent degradation. Mol Cell. 2008;30:403–14.
Sarikas A, Xu X, Field LJ, Pan ZQ. The cullin7 E3 ubiquitin ligase: a novel player in growth control. Cell Cycle. 2008;7:3154–61.
Shi J, Luo L, Eash J, Ibebunjo C, Glass DJ. The SCF-Fbxo40 complex induces IRS1 ubiquitination in skeletal muscle, limiting IGF1 signaling. Dev Cell. 2011;21:835–47.
Song R, Peng W, Zhang Y, Lv F, Wu HK, Guo J, et al. Central role of E3 ubiquitin ligase MG53 in insulin resistance and metabolic disorders. Nature. 2013;494:375–9.
Honors MA, Kinzig KP. The role of insulin resistance in the development of muscle wasting during cancer cachexia. J Cachexia Sarcopenia Muscle. 2012;3:5–11.
Fogelman DR, Holmes H, Mohammed K, Katz MH, Prado CM, Lieffers J, et al. Does IGFR1 inhibition result in increased muscle mass loss in patients undergoing treatment for pancreatic cancer? J Cachexia Sarcopenia Muscle. 2014. doi:10.1007/s13539-014-0145-y.
Schmidt K, von Haehling S, Doehner W, Palus S, Anker SD, Springer J. IGF-1 treatment reduces weight loss and improves outcome in a rat model of cancer cachexia. J Cachexia Sarcopenia Muscle. 2011;2:105–9.
Veasey-Rodrigues H, Parsons HA, Janku F, Naing A, Wheler JJ, Tsimberidou AM, et al. A pilot study of temsirolimus and body composition. J Cachexia Sarcopenia Muscle. 2013;4:259–65.
Han HQ, Zhou X, Mitch WE, Goldberg AL. Myostatin/activin pathway antagonism: molecular basis and therapeutic potential. Int J Biochem Cell Biol. 2013;45:2333–47.
Romanello V, Guadagnin E, Gomes L, Roder I, Sandri C, Petersen Y, et al. Mitochondrial fission and remodelling contributes to muscle atrophy. EMBO J. 2010;29:1774–85.
Lokireddy S, Wijesoma IW, Teng S, Bonala S, Gluckman PD, McFarlane C, et al. The ubiquitin ligase Mul1 induces mitophagy in skeletal muscle in response to muscle-wasting stimuli. Cell Metab. 2012;16:613–24.
Phillips BE, Smith K, Liptrot S, Atherton PJ, Varadhan K, Rennie MJ, et al. Effect of colon cancer and surgical resection on skeletal muscle mitochondrial enzyme activity in colon cancer patients: a pilot study. J Cachexia Sarcopenia Muscle. 2013;4:71–7.
Julienne CM, Dumas JF, Goupille C, Pinault M, Berri C, Collin A, et al. Cancer cachexia is associated with a decrease in skeletal muscle mitochondrial oxidative capacities without alteration of ATP production efficiency. J Cachexia Sarcopenia Muscle. 2012;3:265–75.
Wei B, Dui W, Liu D, Xing Y, Yuan Z, Ji G. MST1, a key player, in enhancing fast skeletal muscle atrophy. BMC Biol. 2013;11:12.
Tsai VW, Husaini Y, Manandhar R, Lee-Ng KK, Zhang HP, Harriott K, et al. Anorexia/cachexia of chronic diseases: a role for the TGF-beta family cytokine MIC-1/GDF15. J Cachexia Sarcopenia Muscle. 2012;3:239–43.
Palus S, von Haehling S, Doehner W, Datta R, Zhang J, Dong JZ, et al. Effect of application route of the ghrelin analog BIM-28131 (RM-131) on body weight and body composition in a rat heart failure model. Int J Cardiol. 2013;168:2369–74.
Lenk K, Palus S, Schur R, Datta R, Dong J, Culler MD, et al. Effect of ghrelin and its analogues, BIM-28131 and BIM-28125, on the expression of myostatin in a rat heart failure model. J Cachexia Sarcopenia Muscle. 2013;4:63–9.
Prather ID, Brown DE, North P, Wilson JR. Clenbuterol: a substitute for anabolic steroids? Med Sci Sports Exerc. 1995;27:1118–21.
Toledo M, Busquets S, Ametller E, Lopez-Soriano FJ, Argiles JM. Sirtuin 1 in skeletal muscle of cachectic tumour-bearing rats: a role in impaired regeneration? J Cachexia Sarcopenia Muscle. 2011;2:57–62.
Greig CA, Johns N, Gray C, MacDonald A, Stephens NA, Skipworth RJ, et al. Phase I/II trial of formoterol fumarate combined with megestrol acetate in cachectic patients with advanced malignancy. Support Care Cancer. 2014;22:1269–75.
Berdeaux R, Stewart R. cAMP signaling in skeletal muscle adaptation: hypertrophy, metabolism, and regeneration. Am J Physiol Endocrinol Metab. 2012;303:E1–17.
von Maltzahn J, Bentzinger CF, Rudnicki MA. Wnt7a-Fzd7 signalling directly activates the Akt/mTOR anabolic growth pathway in skeletal muscle. Nat Cell Biol. 2012;14:186–91.
Minetti GC, Feige JN, Rosenstiel A, Bombard F, Meier V, Werner A, et al. Galphai2 signaling promotes skeletal muscle hypertrophy, myoblast differentiation, and muscle regeneration. Sci Signal. 2011;4:ra80.
Scharf G, Heineke J. Finding good biomarkers for sarcopenia. J Cachexia Sarcopenia Muscle. 2012;3:145–8.
Cesari M, Fielding RA, Pahor M, Goodpaster B, Hellerstein M, van Kan GA, et al. Biomarkers of sarcopenia in clinical trials-recommendations from the International Working Group on Sarcopenia. J Cachexia Sarcopenia Muscle. 2012;3:181–90.
Nedergaard A, Karsdal MA, Sun S, Henriksen K. Serological muscle loss biomarkers: an overview of current concepts and future possibilities. J Cachexia Sarcopenia Muscle. 2013;4:1–17.
Bhasin S, He EJ, Kawakubo M, Schroeder ET, Yarasheski K, Opiteck GJ, et al. N-terminal propeptide of type III procollagen as a biomarker of anabolic response to recombinant human GH and testosterone. J Clin Endocrinol Metab. 2009;94:4224–33.
Chen F, Lam R, Shaywitz D, Hendrickson RC, Opiteck GJ, Wishengrad D, et al. Evaluation of early biomarkers of muscle anabolic response to testosterone. J Cachexia Sarcopenia Muscle. 2011;2:45–56.
Nedergaard A, Sun S, Karsdal MA, Henriksen K, Kjaer M, Lou Y, et al. Type VI collagen turnover-related peptides-novel serological biomarkers of muscle mass and anabolic response to loading in young men. J Cachexia Sarcopenia Muscle. 2013;4:267–75.
Christensen HM, Kistorp C, Schou M, Keller N, Zerahn B, Frystyk J, et al. Prevalence of cachexia in chronic heart failure and characteristics of body composition and metabolic status. Endocrine. 2013;43:626–34.
O’Connell TM. The complex role of branched chain amino acids in diabetes and cancer. Metabolites. 2013;3:931–45.
Patel SS, Molnar MZ, Tayek JA, Ix JH, Noori N, Benner D, et al. Serum creatinine as a marker of muscle mass in chronic kidney disease: results of a cross-sectional study and review of literature. J Cachexia Sarcopenia Muscle. 2013;4:19–29.
Stimpson SA, Turner SM, Clifton LG, Poole JC, Mohammed HA, Shearer TW, et al. Total-body creatine pool size and skeletal muscle mass determination by creatine-(methyl-D3) dilution in rats. J Appl Physiol (1985). 2012;112:1940-8.
Clark RV, Walker AC, O’Connor-Semmes RL, Leonard MS, Miller RR, Stimpson SA, et al. Total body skeletal muscle mass: estimation by creatine (methyl-d3) dilution in humans. J Appl Physiol. 1985;2014:1605–13.
Stimpson SA, Leonard MS, Clifton LG, Poole JC, Turner SM, Shearer TW, et al. Longitudinal changes in total body creatine pool size and skeletal muscle mass using the D-creatine dilution method. J Cachex Sarcopenia Muscle. 2013;4:217–23.
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The authors of this manuscript certify that they comply with the ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia, and Muscle 2010; 1:7–8 (von Haehling S, Morley JE, Coats AJ, and Anker SD). This paper is also published in parallel in the International Journal of Cardiology.
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Palus, S., von Haehling, S. & Springer, J. Muscle wasting: an overview of recent developments in basic research. J Cachexia Sarcopenia Muscle 5, 193–198 (2014). https://doi.org/10.1007/s13539-014-0157-7
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DOI: https://doi.org/10.1007/s13539-014-0157-7