© Springer-Verlag Berlin Heidelberg 2014
10.1007/s13539-014-0149-7

Are we closer to having drugs to treat muscle wasting disease?

John E. Morley , Stephan von Haehling2 and Stefan D. Anker2, 3
(1)
Divisions of Geriatric Medicine and Endocrinology, Saint Louis University School of Medicine, 1402 S. Grand Blvd., M238, St. Louis, MO 63104, USA
(2)
Applied Cachexia Research, Department of Cardiology, Charité Medical School, Campus Virchow-Klinikum, Berlin, Germany
(3)
Department of Innovative Clinical Trials, University Medical Centre Göttingen, Göttingen, Germany
 
 
John E. Morley
Received: 15 April 2014Accepted: 5 May 2014Published online: 28 May 2014
Abstract
The two most common muscle wasting diseases in adults are sarcopenia and cachexia. Despite differences in their pathophysiology, it is believed that both conditions are likely to respond to drugs that increase muscle mass and muscle strength. The current gold standard in this regard is exercise training. This article provides an overview of candidate drugs to treat muscle wasting disease that are available or in development. Drugs highlighted here include ghrelin agonists, selective androgen receptor molecules, megestrol acetate, activin receptor antagonists, espindolol, and fast skeletal muscle troponin inhibitors.
In adults, the two most common muscle wasting diseases are sarcopenia and cachexia [1, 2]. Both conditions are major causes of frailty in older persons [3]. Sarcopenia has now been defined by multiple organizations to be a loss of function, defined by walking speed or distance coupled with a loss of muscle mass [46]. The clinical utility of this definition has been validated [79]. Sarcopenia differs from cachexia in that histologically, it predominately represents a condition primarily due to neurodegeneration coupled with a variety of other factors [10]. In contrast, cachexia is an inflammatory muscle disorder, which is associated with loss of adipose tissue and anorexia [1113]. Despite these differences, it is believed that both conditions are likely to respond to drugs that increase muscle mass and muscle strength.
At present, the gold standard for increasing muscle function is exercise [14, 15]. Following hip fracture high-intensity progressive resistance training decreased mortality and nursing home admissions [16]. In lung cancer, exercise increased the 6 m walk by over 50 m [17]. Exercise in cachexia can reduce inflammation, decrease reactive oxygen species, increase protein synthesis, and decrease protein catabolism [18]. In sarcopenia, while the major effects of exercise appear to be enhancing protein metabolism, there is also evidence that it may improve motor unit function [19]. Exercise also stimulates non-satellite stem cells in skeletal muscle which release growth factors resulting in muscle satellite cell proliferation and differentiation [20].
There is increasing evidence that protein supplementation acts to increase muscle synthesis and that this effect is enhanced in conjunction with exercise [21]. The PROTAGE consensus has supported the need for 1 to 1.5 g/kg of high-quality protein (leucine-enriched, balanced essential amino acids) to restore muscle in persons with sarcopenia [22].
The Cochrane collaboration has shown that in malnourished older persons, protein and energy supplementation produces weight gain and reduces mortality [23]. The INTERCOM trial showed that 24 months of nutritional intervention, coupled with exercise in chronic obstructive pulmonary disease, enhanced muscle strength and 6 min walk distance and decreased hospitalization [24]. Caloric supplementation in persons with heart failure enhanced weight and improved quality of life [25]. Nutritional support following hospitalization in malnourished older persons improves functional limitations [26]. In this editorial, we will review the recent advances in drug therapy for sarcopenia and cachexia as presented at the seventh International Cachexia Conference in Kobe, Japan in December 2013, and place these findings into perspective.
New data on two orexigenics was presented. Of these, ghrelin-like agents represented a major component of the meeting. Ghrelin is produced in the fundus of the stomach and enhances food intake, growth hormone secretion, and muscle mass gain. Its effect on feeding is produced through enhancing nitric oxide synthase activity [27]. It has been shown to increase food intake and stop muscle mass loss in cancer [28]. It has similar positive effects following esophagectomy [29]. Other studies have shown that the ghrelin agonist, capromelin, increased lean mass, tandem walk, and stair climb over 12 months in older sarcopenic individuals [30]. MK-0677, a potent growth hormone-secretagogue mimetic, which works through the ghrelin receptor, improved stair climb and decreased falls in a 24-week study in patients who had had hip fracture [31]. There was, however, an increase in heart failure in the treated group. At the conference, the phase II results of the ghrelin agonist, anamorelin, were presented [32]. Overall, it enhanced body weight, tended to improve handgrip strength, increased appetite and quality of life, and decreased inflammatory markers (C-reactive protein, interleukin-6, and tumor necrosis factor).
Further data on an immunomodulatory, orexigenic drug OHR118 was presented confirming its positive effects on appetite and weight stabilization in a non-placebo-controlled trial [33, 34]. There was no new data on megestrol acetate, a mixed progestagen/testosterone/corticosteroid agent, which increases food intake and weight gain (predominantly fat) in cancer and AIDS [35] and older persons [36]. A combination of megestrol acetate plus thalidomide improved weight gain, quality of life, and grip strength [37]. Megestrol also improved weight in children with cancer [38]. Megestrol is barely absorbed if taken without food, and this can be overcome by using a nanocrystal form [39]. Cannabinoid-like drugs produce less of an increase in food intake and weight gain than megestrol [40]. There is no data available on the effects on appetite and weight gain of the cannabinoid oromucosal spray [41]. While cannabinoids may be excellent drugs for hospice care, it is unlikely that they will prove to be useful orexigenic drugs [42].
Testosterone has been long utilized to improve muscle mass and strength and to a lesser extent function in older persons with sarcopenia [4348]. It has been shown to improve walking distance in persons with heart failure [49, 50]. In combination with a caloric supplement, testosterone markedly decreased hospitalization in frail older persons living in assisted living [51]. Uncertainty of the side effects associated with testosterone therapy has led to the development of selective androgen receptor molecules (SARMs). Enobosarm has been shown to improve lean body mass and stair climb in older men and women [51, 52]. In patients with cancer, enobosarm increased lean mass [53]. At the Cachexia meeting, new data demonstrated that enobosarm improved stair climb in one out of two cancer chemotherapy studies [54]. Their data suggested that in the cancer patients who maintained lean body mass, there was an improvement in survival.
The activin receptor plays a major role through which myostatin inhibits muscle growth [55]. A number of myostatin antibodies have been developed, which at present have not been shown to have a significant effect on muscle gain in humans [56, 57]. Decoy activin II receptors increase lean body mass and bone mineral density [56, 58]. Unfortunately, bleeding associated with this agent appears to limit its usefulness. Inclusion body myositis is a rare autoimmune disease associated with amyloid inclusion bodies that occurs in persons over 50 years of age [59].
Bimagrumab is an activin II receptor antibody. A preliminary study, presented at the seventh International Cachexia Conference, suggests that over a 24-week period, it increased lean body mass, quadriceps strength, and physical performance in persons with sporadic inclusion body myositis [60].
Two cardiological drugs classes have been shown to have effects on muscle function. Perindopril, an angiotensin-converting-enzyme inhibitor, improves distance walked in older persons and in persons with heart failure [61, 62]. Perindopril was used in the Hypertension in the Very Elderly (HYVET) study in which there was a decrease in hip fracture, despite the other agent being a diuretic [63]. Espindolol is a non-specific β12 adrenergic receptor antagonist which has been shown to improve lean mass in rats [64]. In a randomized, double-blind placebo-controlled phase II study in patients with lung or colorectal cancer, espindolol reversed body weight loss seen in the placebo group and maintained lean body and fat mass [65]. It also increased hand grip strength. Trends for functional improvement were also observed.
A new class of drugs is fast skeletal muscle troponin activators (tirasemtiv and CK-2127107). These drugs amplify the response to motor neuron input, increase muscle power, and improve muscle fatigability. Preliminary data has suggested that tirasemtiv may improve function in persons with amyotrophic lateral sclerosis (ALS) [66]. A phase III study in amyotrophic lateral sclerosis is now ongoing. Phase I studies for CK-2127107 have shown it to be safe.
Finally, studies enhancing mitochondrial function by increasing NAD [67] or enhancing Cisd2 function of the outer mitochondrial membrane [68, 69] can enhance muscle function. Bendavia, a novel mitochondria-targeting peptide, restored skeletal muscle fiber type in dogs with heart failure [70].
Since the initiation of the Journal of Cachexia, Sarcopenia, and Muscle in 2010 [71], there has been a remarkable increase in our knowledge regarding the treatment of muscle wasting diseases. It would seem, based on the therapeutic approaches, it is now time to move from using names such as myopenia, sarcopenia, or cachexia to characterize these disorders [72] and to characterize these conditions under the umbrella of “muscle wasting diseases” [73].
Acknowledgements
John E. Morley, Stephan von Haehling, and Stefan D. Anker declare that they have no conflicts of interest regarding the writing of this article. The authors certify that they comply with the ethical guidelines for authorship and publishing of the Journal of Cachexia, Sarcopenia, and Muscle.
References
1.
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.PubMedCentralPubMedCrossRef
2.
von Haehling S, Morley JE, Anker SD. From muscle wasting to sarcopenia and myopenia: update 2012. J Cachexia Sarcopenia Muscle. 2012;3:213–7.CrossRef
3.
Morley JE, Vellas B, van Kan GA, Anker SD, Bauer JM, Bernabei R, et al. Frailty consensus: a call to action. J Am Med Dir Assoc. 2013;14:392–7.PubMedCrossRef
4.
Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, et al. Sarcopenia: european consensus on definition and diagnosis: report of the European working group on sarcopenia in older people. Age Ageing. 2010;39:412–23.PubMedCentralPubMedCrossRef
5.
Morley JE, Abbatecola AM, Argiles JM, Baracos V, Bauer J, Bhasin S, et al. Sarcopenia with limited mobility: an international consensus. J Am Med Dir Assoc. 2011;12:403–9.PubMedCrossRef
6.
Fielding RA, Vellas B, Evans WJ, Bhasin S, Morley JE, Newman AB, et al. Sarcopenia: an undiagnosed condition in older adults. Current consensus definition: prevalence, etiology, and consequences. International working group on sarcopenia. J Am Med Dir Assoc. 2011;12:249–56.PubMedCrossRef
7.
Lee WJ, Liu LK, Peng LN, Lin MH, Chen LK, ILAS Research Group. Comparisons of sarcopenia defined by IWGS and EWGSOP criteria among older people: Results from the I-Lan longitudinal aging study. J Am Med Dir Assoc. 2013;14:528.e1-7.PubMed
8.
Malmstrom TK, Miller DK, Herning MM, Morley JE. Low appendicular skeletal muscle mass (ASM) with limited mobility and poor health outcomes in middle-aged African Americans. J Cachexia Sarcopenia Muscle. 2013;4:179–86.PubMedCentralPubMedCrossRef
9.
Landi F, Liperoti R, Fusco D, Mastropaolo S, Quattrociocchi D, Proia A, et al. Sarcopenia and mortality among older nursing home residents. J Am Med Dir Assoc. 2012;13:121–6.PubMedCrossRef
10.
Morley JE. Weight loss in older persons: new therapeutic approaches. Curr Pharm Des. 2007;13:3637–47.PubMedCrossRef
11.
Argiles JM, Anker SD, Evans WJ, Morley JE, Fearon KC, Strasser F, et al. Consensus on cachexia definitions. J Am Med Dir Assoc. 2010;11:229–30.PubMedCrossRef
12.
Morley JE, Anker SD, Evans WJ. Cachexia and aging: an update based on the Fourth International Cachexia meeting. J Nutr Health Aging. 2009;13:47–55.PubMedCrossRef
13.
Evans WJ, Morley JE, Argiles J, Bales C, Baracos V, Guttridge D, et al. Cachexia: a new definition. Clin Nutr. 2008;27:793–9.PubMedCrossRef
14.
Argiles JM, Busquets S, Lopez-Soriano FJ, Costelli P, Penna F. Are there any benefits of exercise training in cancer cachexia? J Cachexia Sarcopenia Muscle. 2012;3:73–6.PubMedCentralPubMedCrossRef
15.
Cadone Cadore EL, Izquierdo M. New strategies for the concurrent strength-, power-, and endurance-training prescription in elderly individuals. J Am Med Dir Assoc. 2013;14:623–4.CrossRef
16.
Singh NA, Quine S, Clemson LM, Williams EJ, Williamson DA, Stavrinos TM, et al. Effects of high-intensity progressive resistance training and targeted multidisciplinary treatment of frailty on mortality and nursing home admissions after hip fracture: a randomized controlled trial. J Am Med Dir Assoc. 2012;13:24–30.PubMedCrossRef
17.
Cavalheri V, Tahirah F, Nonoyama M, Jenkins S, Hill K. Exercise training for people following lung resection for non-small cell lung cancer – a Cochrane systematic review. Cancer Treat Rev 2013
18.
Gould DW, Lahart I, Carmichael AR, Koutedakis Y, Metsios GS. Cancer cachexia prevention via physical exercise: molecular mechanisms. J Cachexia Sarcopenia Muscle. 2013;4:111–24.PubMedCentralPubMedCrossRef
19.
Fragala MS, Jajtner AR, Beyer KS, Townsend JR, Emerson NS, Scanlon TC, et al. Biomarkers of muscle quality: N-terminal propeptide of type III procollagen and C-terminal agrin fragment responses to resistance exercise training in older adults. J Cachexia Sarcopenia Muscle 2013, in press. doi: 10.​1007/​s13539-013-0120-z.
20.
Boppart MD, De Lisio M, Zou K, Huntsman HD. Defining role for non-satellite stem cells in the regulation of muscle repair following exercise. Front Physiol. 2013;4:310.PubMedCentralPubMed
21.
Tieland M, van de Rest O, Dirks ML, van der Zwaluw N, Mensink M, van Loon LJ, et al. Protein supplementation improves physical performance in frail elderly people: a randomized, double-blind, placebo-controlled trial. J Am Med Dir Assoc. 2012;13:720–6.PubMedCrossRef
22.
Bauer J, Biolo G, Cederholm T, Cesari M, Cruz-Jentoft AJ, Morley JE, et al. Evidence-based recommendations for optimal dietary protein intake in older people: a position paper from the PROT-AGE study group. J Am Med Dir Assoc. 2013;14:542–59.PubMedCrossRef
23.
Milne AC, Potter J, Vivanti A, Avenell A. Protein and energy supplementation in elderly people at risk from malnutrition. Cochrane Database Syst Rev 2009 (2):CD003288
24.
van Wetering C, Hoogendoorn M, Broekhuizen R, Geraerts-Keeris GJ, de Munck DR, Rutten-van Mölken MP, et al. Efficacy and costs of nutritional rehabilitation in muscle-wasted patients with chronic obstructive pulmonary disease in a community-based setting: a prespecified subgroup analysis of the INTERCOM trial. J Am Med Dir Assoc. 2010;11:179–87.PubMedCrossRef
25.
Rozentryt P, von Haehling S, Lainscak M, Nowak JU, Kalantar-Zadeh K, Polonski L, et al. The effects of a high-caloric protein-rich oral nutritional supplement in patients with chronic heart failure and cachexia on quality of life, body composition, and inflammation markers: a randomized, double-blind pilot study. J Cachexia Sarcopenia Muscle. 2010;1:35–42.PubMedCentralPubMedCrossRef
26.
Neelemaat F, Bosmans JE, Thijs A, Seidell JC, van Bokhorst-de van der Schuren MA. Post-discharge nutritional support in malnourished elderly individuals improves functional limitations. J Am Med Dir Assoc. 2011;12:295–301.PubMedCrossRef
27.
Gaskin FS, Farr SA, Banks WA, Kumar VB, Morley JE. Ghrelin-induced feeding is dependent on nitric oxide. Peptides. 2008;24:913–8.CrossRef
28.
Argiles JM, Stemmler B. The potential of ghrelin in the treatment of cancer cachexia. Expert Opin Biol Ther. 2013;13:67–76.PubMedCrossRef
29.
Miyazaki T, Tanaka N, Hirai H, Yokobori T, Sano A, Sakai M, et al. Ghrelin level and body weight loss after esophagectomy for esophageal cancer. J Surg Res. 2012;176:74–8.PubMedCrossRef
30.
White HK, Petrie CD, Landschulz W, MacLean D, Taylor A, Lyles K, et al. Effects of an oral growth hormone secretagogue in older adults. J Clin Endocrinol Metab. 2009;94:1198–206.PubMedCrossRef
31.
Adunsky A, Chandler J, Heyden N, Lutkiewicz J, Scott BB, Berd Y, et al. MK-0677 (ibutamoren mesylate) for the treatment of patients recovering from hip fractures: a multicenter, randomized, placebo-controlled phase IIb study. Arch Gerontol Geriatr. 2011;53:183–9.PubMedCrossRef
32.
Temel J, Bondarde S, Jain M, Yun Y, Duus E, Allen S, et al. Efficacy and safety results from a phase II study of anamorelin HC21, a ghrelin receptor agonist, in NSCLC patients. J Cachexia Sarcopenia Muscle. 2013;4:334. doi:10.​1007/​s13539-013-0123-9. Abstract 5-01.
33.
Chasen M, Hirschman SZ, Bhargava R. Phase II study of the novel peptide-nucleic acid OHR118 in the management of cancer-related anorexia/cachexia. J Am Med Dir Assoc. 2011;12:62–7.PubMedCrossRef
34.
Chasen M, Bhargava R, Hirschmann S, Taraporewala I. Phase II study of OHR/AVR 118 in anorexia–cachexia. J Cachexia Sarcopenia Muscle. 2013;4:335. doi:10.​1007/​s13539-013-0123-9. Abstract 5-04.
35.
Ruiz Garcia V, López-Briz E, Carbonell Sanchis R, Gonzalvez Perales JL, Bort-Marti S. Megestrol acetate for treatment of anorexia-cachexia syndrome. Cochrane Database Syst Rev. 2013;3, CD004310.PubMed
36.
Karcic E, Philpot C, Morley JE. Treating malnutrition with megestrol acetate: literature review and review of our experience. J Nutr Health Aging. 2002;6:191–200.PubMed
37.
Wen HS, Li X, Cao YZ, Zhang CC, Yang F, Shi YM, et al. Clinical studies on the treatment of cancer cachexia with megestrol acetate plus thalidomide. Chemotherapy. 2012;58:461–7.PubMedCrossRef
38.
Cuvelier GD, Baker TJ, Peddi EF, Casey LM, Lambert PJ, Distefano DS, et al. A randomized, double-blind, placebo-controlled clinical trial of megestrol acetate as an appetite stimulant in children with weight loss due to cancer and/or cancer therapy. Pediatr Blood Cancer 2013, in press. doi: 10.​1002/​pbc.​24828.
39.
Yeh SS, Schuster MW. Megestrol acetate in cachexia and anorexia. Int J Nanomedicine. 2006;1:411–6.PubMedCentralPubMedCrossRef
40.
Jatoi A, Windschitl HE, Loprinzi CL, Sloan JA, Dakhil SR, Mailliard JA, et al. Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study. J Clin Oncol. 2002;20:567–73.PubMedCrossRef
41.
Schoedel KA, Harrison SJ. Subjective and physiological effects of oromucosal sprays containing cannabinoids (nabiximols): potentials and limitations for psychosis research. Curr Pharm Des. 2012;18:5008–14.PubMedCrossRef
42.
Morley JE. End-of-life care in the nursing home. J Am Med Dir Assoc. 2011;12:77–83.PubMedCrossRef
43.
Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ, Gooren LJ. et al; European Association of Urology; European Academy of Andrology; American Society of Andrology. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. Eur Urol. 2009;55:121–30.PubMedCrossRef
44.
Morley JE. Androgens and aging. Maturitas. 2001;38:61–71.PubMedCrossRef
45.
Srinivas-Shankar U, Roberts SA, Connolly MJ, O’Connell MD, Adams JE, Oldham JA, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2010;95:639–50.PubMedCrossRef
46.
Page ST, Amory JK, Bowman FD, Anawalt BD, Matsumoto AM, Bremner WJ, et al. Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. J Clin Endocrinol Metab. 2005;90:1502–10.PubMedCrossRef
47.
Kenny AM, Kleppinger A, Annis K, Rathier M, Browner B, Judge JO, et al. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels, low bone mass, and physical frailty. J Am Geriatr Soc. 2010;58:1134–43.PubMedCentralPubMedCrossRef
48.
Travison TG, Basaria S, Storer TW, Jette AM, Miciek R, Farwell WR, et al. Clinical meaningfulness of the changes in muscle performance and physical function associated with testosterone administration in older men with mobility limitation. J Gerontol A Biol Sci Med Sci. 2011;66:1090–9.PubMedCrossRef
49.
Caminiti G, Volterrani M, Iellamo F, Marazzi G, Massaro R, Miceli M, et al. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure: a double-blind, placebo-controlled, randomized study. J Am Coll Cardiol. 2009;54:919–27.PubMedCrossRef
50.
Iellamo F, Volterrano M, Caminiti G, Karam R, Massaro R, Fini M, et al. Testosterone therapy in women with chronic heart failure: a pilot double-blind, randomized, placebo-controlled study. J Am Coll Cardiol. 2010;56:1310–6.PubMedCrossRef
51.
Chapman IM, Visvanathan R, Hammond AJ, Morley JE, Field JB, Tai K, et al. Effect of testosterone and a nutritional supplement, alone and in combination, on hospital admissions in undernourished older men and women. Am J Clin Nutr. 2009;89:880–9.PubMedCrossRef
52.
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.PubMedCentralPubMedCrossRef
53.
Dobs AS, Boccia RV, Croot CC, Gabrial NY, Dalton JT, Hancock ML, et al. Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomized controlled phase 2 trial. Lancet Oncol. 2013;14:335–45.PubMedCrossRef
54.
Steiner MS. Enobasarm, a selective androgen receptor modulator, increases lean body mass in advanced non-small cell lung cancer patients in two pivotal, international phase 3 trials. J Cachexia Sarcopenia Muscle. 2013;4:68. doi:10.​1007/​s13539-013-0123-9. Abstract 5-15.
55.
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.PubMedCentralPubMedCrossRef
56.
Morley JE. Developing novel therapeutic approaches to frailty. Curr Pharm Des. 2009;15:3384–95.PubMedCrossRef
57.
Tisdale MJ. Reversing cachexia. Cell. 2010;142:511–2.PubMedCrossRef
58.
Attie KM, Brogstein NG, Yang Y, Condon CH, Wilson DM, Pearsall AE, et al. A single ascending-dose study of muscle regulator ACE-031 in healthy volunteers. Muscle Nerve. 2013;47:416–23.PubMedCrossRef
59.
Machado P, Brady S, Hanna MG. Update in inclusion body myositis. Curr Opin Rheumatol. 2013;25:763–71.PubMedCrossRef
60.
Rooks D. Targeting myostatin and activin receptors. Abstracts, 7th Cachexia Conference. Kobe, 2013, p.49.
61.
Sumukadas D, Witham MD, Struthers AD, McMurdo ME. Effect of perindopril on physical function in elderly people with functional impairment: a randomized controlled trial. CMAJ. 2007;177:867–74.PubMedCentralPubMedCrossRef
62.
Hutcheon SD, Gillespie ND, Crombie IK, Struthers AD, McMurdo ME. Perindopril improves six minute walking distance in older patients with left ventricular systolic dysfunction: a randomized double blind placebo controlled trial. Heart. 2002;88:373–7.PubMedCentralPubMedCrossRef
63.
Peters R, Beckett N, Burch L, de Vernejoul MC, Liu L, Duggan J, et al. The effect of treatment based on diuretic (indapamide) +/- ACE inhibitor (perindopril) on fractures in the Hypertension in the Very Elderly Trial (HYVET). Age Ageing. 2010;39:609–16.PubMedCrossRef
64.
Steward Coats AJ, Srinivasan Surendran J, Chicarmana H, Vangipuram SR, Bhatt NN, Jain M, et al. The ACT-ONE trial, a multicentre, randomised, double-blind, placebo-controlled dose-finding study of the anabolic/catabolic transforming agent, MT-102 in subjects with cachexia related to stage III and IV non-small cell lung cancer and colorectal cancer: study design. J Cachexia Sarcopenia Muscle. 2011;2:201–7.CrossRef
65.
Coats AJS. Novel beta blockers. Abstracts, 7th Cachexia Conference. Kobe 2013, p.51.
66.
Malik F. Fast skeletal muscle troponin activators and their application to disease-preclinical characterization. Abstracts, 7th Cachexia Conference. Kobe, 2013, p.50.
67.
Gomes AP, Price N, Ling AJY, Moslehi JJ, Montgomery MK, Rajman L, et al. Declining NAD + induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013;155:1624–38.PubMedCrossRef
68.
Chen YF, Wu CY, Kirby R, Kao CH, Tsai TF. A role for the CISD2 gene in lifespan control and human disease. Ann NY Acad Sci. 2010;1201:58–64.PubMedCrossRef
69.
Chen YF. The mitochondrial contribution to muscle atrophy in aging and disease. Abstracts, 7th Cachexia Conference. Kobe, 2013, p.37.
70.
Sabbah MN. Long-term therapy with Bendavia (MTP-131), a novel mitochondria-targeting peptide, normalizes skeletal muscle fiber type composition in dogs with chronic heart failure. Abstracts, 7th Cachexia Conference. Kobe, 2013, p.54.
71.
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.CrossRef
72.
Fearon K, Evans WJ, Anker SD. Myopenia—a new universal term for muscle wasting. J Cachexia Sarcopenia Muscle. 2011;2:1–3.73.PubMedCentralPubMedCrossRef
73.
Anker SD, Coats AJ, Morley JE, Rosano G, Bernabei R, von Haehling S, et al. Muscle wasting disease: a proposal for a new disease classification. J Cachexia Sarcopenia Muscle. 2014;5:1–3.PubMedCentralPubMedCrossRef
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