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Myopenia and precision (P4) medicine

John E. Morley1,*, Stefan D. Anker2

Version of Record online: 24 SEP 2017

DOI: 10.1002/jcsm.12231

How to Cite

Morley, J. E., and Anker, S. D. (2017) Myopenia and precision (P4) medicine. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12231.

Author Information

Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, MO, USA
Division of Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Centre Göttingen, Göttingen, Germany

*Correspondence to: John E. Morley, MB, BCh, Division of Geriatric Medicine, Saint Louis University School of Medicine, 1402 S. Grand Blvd., M238, St. Louis, MO 63104, USA. Email: john.morley@health.slu.edu


Precision (P4) medicine represents a new medical paradigm that focuses on Personalized, Predictive, Preventive and Participatory approaches. The P4 paradigm is particularly appropriate for moving the care of persons with myopenia forward. Muscular dystrophies are clearly a set of genetically different diseases where genomics are the basis of diagnosis, and genetic modulation via DNA, oligonucleotides and clustered regularly interspaced short palendronic repeats hold great potential for a cure. The utility of personalized genomics for sarcopenia coupled with utilizing a predictive approach for the diagnosis with early preventive strategies is a key to improving sarcopenic outcomes. The importance of understanding different levels of patient enthusiasm and different responses to exercise should guide the participatory phase of sarcopenic treatment. In the case of cachexia, understanding the effects of the different therapies now available through the P4 approach on muscle wasting is a key to management strategies.

“I am launching a new Precision Medicine Initiative to bring us closer to curing disease like cancer and diabetes – and to give us all access to personalized information we need to keep ourselves and our families healthier.”

~President Obama

State of the Union

January 20, 2015

Myopenia was defined as clinically relevant muscle wasting associated with impairment of muscle function and/or an increase in morbidity and/or mortality.[1, 2] Conditions producing myopenia could be either congenital or acquired. In adults, the two most common causes of myopenia are cachexia[3] and sarcopenia.[4]

Precision (P4) medicine or patient-centred medicine is a concept developed by the biologist, Leory Hood.[5] While he stressed the importance of genomics, metabolimics, transcriptomics and proteomics in developing a personalized profile for each patient to allow more precise care, it also stresses the importance of recognizing the different possible causes of a process in the individual person and the importance of early recognition and prevention of those at risk and the concept that the individual should make their own decision about treatment choices and be actively involved in her own management.[6] The tenets of this approach can be summarized by the concept of P4 medicine:


Utilizing genomics and other molecular diagnostic tools, as well as environmental and lifestyle characteristics to create a personal diagnostic and management plan.


Utilize this available information to recognize the risk of an individual developing a specific disease and the likelihood of them responding to different treatments.


Based on this knowledge, each individual has their own primary and secondary prevention plans.


The data is shared with the individual who then participates in choosing the treatment choices. In theory, this will lead to better compliance.

While the full implementation of P4 medicine is clearly in the future, many of the components are becoming increasingly available and can proactively be introduced at this time. Myopenia represents a set of conditions where rapid uptake of P4 medicine can occur.

Muscular dystrophy

Muscular dystrophies consist of a variety of genetic disorders resulting in weakening and breakdown of skeletal muscle.[7] There are nine main categories of muscular dystrophy and over 30 subtypes. These diseases are related to alterations in the structure or function of the dystrophin protein. They are due to mutations in genes having a critical role in muscle function.

Being able to recognize the genetic mutation that causes each of the forms of muscle dystrophy has opened up a variety of methods by which these genes can be manipulated to reverse the disease process. Both in vitro and studies in animal models have proven this to be possible. Duchenne muscular dystrophy is due to loss of function in the dystrophin gene. Predominantly, this is due to disruption in the dystrophin protein reading frame.[7, 8] This allows a number of techniques to be developed to provide a precise correction of the dystrophin gene. The length of the dystrophin gene limits the possibility of augmenting the total gene active with cDNAs. For this reason, both viral vectors (adeno-associated and lentiviral) have been developed to introduce truncated microdystrophin or microutrophin into the DNA.[9, 10] Sleeping beauty transposons represent a nonviral vector approach to insert these microgenes into the genome.[11] This approach has led to the improvement of dystrophin function to some extent, but not total cure of the disease. Aartsma-Rus and Krieg[12, 13] developed eteplirsen, an oligonucleotide that interferes with the splicing process allowing the reading frame to be restored. This leads to a partially functional dystrophin. The FDA, based on small clinical trials, approved eteplirsen for the treatment of Duchene muscular dystrophy.

Two programmable nucleases, transcription activator-like effector nuclease[14] and clustered regularly interspaced short palendronic repeats (CRISPR),[15] have been demonstrated to be able to produce gene correction or gene knockout in human stem cells. Adeno-associated virus-mediated and RNA guide CRISPR/Cas 9 systems of gene therapy have been developed that produce partially functional dystrophin genes and improve function in the mdx mouse.[16-18] This approach also works in pluripotent human satellite cells.[19, 20] It is important to recognize that CRISPR gene editing also causes unintended mutations. The precision medicine approaches to treating muscular dystrophy are illustrated in Figure 1.[21]

Figure 1.

Figure 1.

Mechanisms to modulate the gene in muscular dystrophy.

P4 medicine in sarcopenia

In the Personalized (P1) approach to sarcopenia, a number of allele variations have been identified to be associated with muscle mass and strength.[22-26] These include myostatin (GDF8, K133R), CNTF and its receptor, vitamin D receptor (VDR Bsml), angiotensin-converting medicine, androgen receptor gene (CAG repeats), cyclin-dependent kinase inhibitor 1A, MOD1 and P53 which decreases satellite activation. In addition, small babies predict the presence of low grip strength at 70 years of age.[27]

The Predictive (P2) phase includes a number of screening tests for early sarcopenia that have been developed. For example, Harada et al.[28] used sex, age, BMI and adiponectin and sialic acid levels to have a high sensitivity for persons with sarcopenia. In addition, the simple SARC-F screen (Table 1) has been shown to be highly predictive of persons who are at risk of developing sarcopenia, loss of muscle function, disability and hospitalization. Further, persons with sarcopenia having accelerated loss of muscle when renal cancer is treated with sorafenib is recognized.[29-40] Sorafenib also has an increase in toxicity when given to sarcopenia patient with hepatocellular cancer.[41]

Table 1. SARC-F screen for sarcopenia
  1. aSARC-F scale scores range from 0 to 10 (i.e. 0–2 points for each item; 0 = best to 10 = worst) and represent no sarcopenia (0–3) and sarcopenia.[4-10]
StrengthHow much difficulty do you have in lifting and carrying 10 pounds?None = 0
Some = 1
A lot or unable = 2
Assistance in walkingHow much difficulty do you have walking across a room?None = 0
Some = 1
A lot, use aids or unable = 2
Rise from a chairHow much difficulty do you have transferring from a chair or bed?None = 0
Some = 1
A lot or unable without help = 2
Climb stairsHow much difficulty do you have climbing a flight of 10 stairs?None = 0
Some = 1
A lot or unable = 2
FallsHow many times have you fallen in the last year?None = 0
One to three falls = 1
Four or more falls = 2
Table 2. Patient-centred precision (P4) medicine applied to sarcopenia
P1: Predictive:Recognize persons at risk for sarcopenia based on genetic make-up or being a small baby at birth
P2: Preventive:Use SARC-F to screen and then introduce resistance exercise, protein supplementation and vitamin D
P3: Personalized:Diagnose sarcopenia and identify and manage specific causes, for example, poor blood flow to muscles, low testosterone, cytokine excess, obesity, neuropathic, diabetes mellitus and excess myostatin
P4: Participation:

Recognition and identification of specific exercise approaches based on the individual understanding of the person's muscle type.

Work with the person to increase acceptability and understanding of treatment plan and increase compliance

In the Preventive (P3) phase of P4 medicine (Table 2), early recognition that those at increased risk of sarcopenia should lead to advice to increase resistance exercise[42-46] utilizes leucine-enriched essential amino acids[47-49] or possibly hydroxymethyl butyrate[50-53] and in persons not getting adequate sunlight to provide 1000 IU vitamin D daily.[54-56]

This requires that a clear diagnosis of the cause of sarcopenia should be made early in the process. This includes measuring muscle mass and function[57-61] and a muscle biopsy or measuring C-agrin to determine whether the person has predominantly neuropathic muscle loss or some other cause.[62-64] Recognition of whether the person has obese sarcopenia represents another part of personalization.[65-67] A decrease in bioavailable testosterone or low dehydroepiandrosterone levels as a cause of muscle loss should be identified.[68-71] These persons are more likely to respond to testosterone therapy,[72-74] particularly if they have congestive heart failure.[75-80] Blood flow to muscles is a key cause of muscle loss, especially in diabetes mellitus.[81-84] Finally, cytokine excess plays a major role in muscle loss.[85, 86]

Animals lacking myostatin have increased muscle mass.[87] Myostatin binds to the activin II receptors with higher affinity for the IIb affinity.[88] In older persons, stem cell expression of myostatin is higher than in younger persons.[89] However, the levels of myostatin in younger and older persons vary considerably in different individuals suggesting that individuals may have their own specific myostatin levels.[90] LY2495655, a myostatin antibody, increased muscle mass and improved muscle function.[91] Other studies have shown less dramatic effects of myostatin antibodies in older persons with sarcopenia.[92] A decoy receptor for activin II receptors increased muscle mass was associated with bleeding.[93] Persons who have haemorrhagic telangiectasia have an abnormal activin receptor I.[94] Animal studies suggest that muscle effects are due to the activin II receptor.[95] In humans with sarcopenia related to femoral fracture, there are increased levels of myostatin and increased phosphorylation of Smad proteins.[96] These findings suggest that anti-myostatin antibodies should be preferentially considered in sarcopenic individuals with muscle elevations of the myostatin/Smad pathways, a perfect example of P4 medicine. Preliminary studies in goats and rabbits using CRISPR/Cas9 to knock out myostatin increased muscle mass but had a number of side effects.[97]

The final component of P4 medicine is Participatory. Patients need to be able to choose which therapies they would prefer. An important component of this is to recognize that response to exercise varies enormously in individuals, and 30% of this appears to be related to the person's genetic make-up.[98] Churchward et al.[99] have suggested that despite this, all persons have some degree of response to resistance exercise. In the end, the person's compliance with the exercise and dietary programs remains the major factor deciding the outcome of the therapeutic program. This was nicely shown in the ‘Look Ahead’ study, where those persons in the upper quartile of time spent exercising a week had significantly better outcomes than those in the lowest quartile.[100]


Cachexia is a multifactorial syndrome due to a variety of conditions leading to inflammatory muscle mass loss.[101] While the molecular basis of muscle wasting in cachexia is well established in animals (i.e. cytokines such as TNF, IL-1, IL-6, interferon, TNF receptor adaptor protein, associated with the ubiquitin–proteasome system and elevated myostatin), it is less well established in humans.[102, 103] The variability in humans is the result of the multiple different disease causes and genetic variability.

Management of cancer is one of the leading areas in precision medicine. As already noted, muscle function both affects the side effects of cancer chemotherapy, and the therapy can accelerate muscle loss. Immune checkpoint therapy with its release of a cascade of immune systems to attack the cancer is likely to see an acceleration of muscle loss.[104] For long-term recovery, it will be important to attempt to protect muscle during these times.

It is recognized that persons admitted to hospital lose as much as a kilogram of muscle in 3 days and that those with sepsis lose even more muscle mass and long-term muscle function.[105, 106] As part of personalized medicine, it is essential to see that hospitalized patients get adequate amounts of protein (1.5 to 2 g/day) and have resistance exercise to maintain their muscle mass – neither of these approaches are common in hospitals. There is data to support that ICU patients who get out of bed daily have better outcomes.[107]


P4 medicine represents an explosive new way to approach myopenia. It is clear that the old fashioned approach to medicine that has been disease based will change over the next decade to a personalized medicine where the person's genetic make-up and other molecular characteristics will determine the approach to the management of disease. To incorporate this into medical practice, we will need to utilize computer-assisted management. The medicine of today lacks precision in diagnosis and therapeutics—personalized medicine will alter modern medicine placing the emphasis on the patients, their genes, their environment, their response to therapies and their participation in their own care. The myopenias represent an area in which a rapid understanding and deployment of P4 medicine will improve the quality of life of large numbers of persons.

Ethics statement

The authors certify that they comply with the ethical guidelines for authorship and publishing of the Journal of Cachexia, Sarcopenia and Muscle.[108]


1Anker SD, Coats AJ, Morley JE, Rosano G, Bernabei R, von Haehling S, Kalantar-Zadeh K. Muscle wasting disease: a proposal for a new disease classification. J Cachexia Sarcopenia Muscle 2014;5:13.2Fearon K, Evans WJ, Anker SD. Myopenia—a new universal term for muscle wasting. J Cachexia Sarcopenia Muscle 2011;2:13.3Evans WJ, Morley JE, Argiles J, Bales C, Baracos V, Guttridge D, Jatoi A, et al. Cachexia: a new definition. Clin Nutr 2008;27:793799.4Morley 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;12:403409.5Hood L. Systems biology and p4 medicine: past, present, and future. Rambam Maimonides Med J 2013;4: e0012.6Morley JE, Vellas B. Patient-centered (P4) medicine and the older person. J Am Med Dir Assoc 2017;18:455459.7Li HL, Fujimoto N, Sasakawa N, Shirai S, Ohkame T, Sakuma T, et al. Precise correction of the dystrophin gene in Duchenne muscular dystrophy patient induced pluripotent stem cells by TALEN and CRISPR-Cas9. Stem Cell Reports 2015;4:143154.8Wilton SD, Fletcher S. Splice modification to restore functional dystrophin synthesis in Duchenne muscular dystrophy. Curr Pharm Des 2010;16:9881001.9Okada T, Takeda S. Current challenges and future directions in recombinant AAV-mediated gene therapy of Duchenne muscular dystrophy. Pharmacueticals (Basel) 2013;6:813836.10Pichavant C, Aartsma-Rus A, Clemens PR, Davies KE, Dickson G, Takeda S, et al. Current status of pharmaceutical and genetic therapeutic approaches to treat DMD. Mol Ther 2011;19:830840.11Filareto A, Parker S, Darabi R, Borges L, Iacovino M, Schaaf T, et al. An ex vivo gene therapy approach to treat muscular dystrophy using inducible pluripotent stem cells. Nat Commun 2013;4:1549.12Aartsma-Rus A, Krieg AM. FDA approves eteplirsen for Duchenne muscular dystrophy: the next chapter in the eteplirsen saga. Nucleic Acid Ther 2017;27:13.13Aartsma-Rus A, Fokkema I, Verschuuren J, Ginjaar I, van Deutekom J, van Ommen GJ, den Dunnen JT. Theoretic applicability of antisense-mediated exon skipping for Duchenne muscular dystrophy mutations. Hum Mutat 2009;30:293299.14Hotta A. Genome editing gene therapy for Duchenne muscular dystrophy. J Neuromuscul Dis 2015;2:343355.15Gee P, Xu H, Hotta A. Cellular reprogramming, genome editing, and alternative CRISPR Cas9 technologies for precise gene therapy of Duchenne muscular dystrophy. Stem Cells Int 2017;8765154. Doi: https://doi.org/10.1155/2017/8765154; Epub May 15, 2017.16Wang JZ, Wu P, Shi ZM, Xu YL, Liu ZJ. The AAV-mediated and RNA-guided CRISPR/Cas9 system for gene therapy of DMD and BMD. Brain Dev 2017; https://doi.org/10.1016/j.braindev.2017.03.024(In press).17Xu L, Park KH, Zhao L, Xu J, El Refaey M, Gao Y, et al. CRISPR-mediated genome editing restores dystrophin expression and function in mdx mice. Mol Ther 2016;24:564569.18Tabebordbar M, Zhu K, Cheng JKW, Chew WL, Widrick JJ, Winston XY, et al. In vivo gene editing in dystrophic mouse muscle and muscle stem cells. Science 2016;351:407411.19Calos MP. The CRISPR way to think about Duchenne's. N Engl J Med 2016;374:16841687.20Young CS, Hicks MR, Ermolova NV, Nakano H, Jan M, Younesi S, et al. A single CRISPR-Cas9 deletion strategy that targets the majority of DMD patients resotres dystropin function in hiPSC-derived muscle cells. Cell Stem Cell 2016;18:533540.21Saada YB, Dib C, Lipinski M, Vassetzky YS. Review: genome- and cell-based strategies in therapy of muscular dystrophies. Protein Bio Msu 2016;https://doi.org/10.1134/S000629791607004X.
22Morley JE. Pharmacologic options for the treatment of sarcopenia. Calcif Tissue Int 2016;98:319333.23Walsh S, Ludlow AT, Metter EJ, Ferrucci L, Roth SM. Replication study of the vitamin D receptor (VDR) genotype association with skeletal muscle traits and sarcopenia. Aging Clin Exp Res 2016;28:435442.24Corsi AM, Ferrucci L, Gozzini A, Tanini A, Brandi ML. Myostatin polymorphisms and age-related sarcopenia in the Italian population. J Am Geriatr Soc 2002;50:1463.25Baldelli S, Ciriolo MR. Altered S-nitrosylation of p53 is responsible for impaired antioxidant response in skeletal muscle during aging. Aging (Albany NY) 2016;8:34503467.26Marzetti E, Calvani R, Cesari M, Buford TW, Lorenzi M, Behnke BJ, Leeuwenburgh C. Mitochondrial dysfunction and sarcopenia of aging: from signaling pathways to clinical trials. Int J Biochem Cell Biol 2013;45:22882301.27Sayer AA, Syddall HE, Gilbody HJ, Dennison EM, Cooper C. Does sarcopenia originate in early life? Findings from the Hertfordshire cohort study. J Gerontol A Biol Sci Med Sci 2004;59:M930M934.28Harada H, Kai H, Shibata R, Niiyama H, Nishiyama Y, Murohara T, et al. New diagnostic index for sarcopenia in patients with cardiovascular diseases. PLoS One 2017;12: e0178123.29Rolland Y, Dupuy C, Abellan Van Kan G, Cesari M, Vellas B, Faruch M, et al. Sarcopenia screened by the SARC-F questionnaire and physical performances of elderly women: a cross-sectional study. J Am Med Dir Assoc 2017;18: https://doi.org/10.1016/j.jamda.2016.10.019. [Epub ahead of print].30Tanaka S, Kamiya K, Hamazaki N, Matsuzawa R, Nozaki K, Maekawa E, et al. Utility of SARC-F for assessing physical function in elderly patients with cardiovascular disease. J Am Med Dir Assoc 2017;18:176181.31Parra-Rodriguez L, Szleijf C, Garcia-Gonzalez AI, Malmstrom TK, Cruz-Arenas E, Rosas-Carrasco O. Cross-cultural adaptation and validation of the Spanish-language version of the SARC-F to assess sarcopenia in Mexican community-dwelling older adults. J Am Med Dir Assoc 2016;17:11421146.32Wu TY, Liaw CK, Chen FC, Kuo KL, Chie WC, Yang RS. Sarcopenia screened with SARC-F questionnaire is associated with quality of life and 4-year mortality. J Am Med Dir Assoc 2016;17:11291135.33Barbosa-Silva TG, Menezes AM, Bielemann RM, Malmstrom TK, Gonzalez MC. Grupo de Estudos em Composiçăo Corporal e Nutriçăo (COCONUT). J Am Med Dir Assoc 2016;17:11361141.34Liccini A, Malmstrom TK. Frailty and sarcopenia as predictors of adverse health outcomes in persons with diabetes mellitus. J Am Med Dir Assoc 2016;17:846851.35Malmstrom TK, Miller DK, Simonsick EM, Ferrucci L, Morley JE. SARC-F: a symptom score to predict persons with sarcopenia at risk for poor functional outcomes. J Cachexia Sarcopenia Muscle 2016;7:2836.36Woo J, Leung J, Morley JE. Defining sarcopenia in terms of incident adverse outcomes. J Am Med Dir Assoc 2015;16:247252.37Woo J, Leung J, Morley JE. Validating the SARC-F: a suitable community screening tool for sarcopenia? J Am Med Dir Assoc 2014;15:630634.38Cao L, Chen S, Zou C, Ding X, Gao L, Liao Z, et al. A pilot study of the SARC-F scale on screening sarcopenia and physical disability in the Chinese older people. J Nutr Health Aging 2014;18:277283.39Malmstrom TK, Morley JE. SARC-F: a simple questionnaire to rapidly diagnose sarcopenia. J Am Med Dir Assoc 2013;14:531532.40Antoun S, Birdsell L, Sawyer MB, Venner P, Escudier B, Baracos VE. Association of skeletal muscle wasting with treatment with sorafenib in patients with advanced renal cell carcinoma: results from a placebo-controlled study. J Clin Oncol 2010;28:10541060.41Mir O, Coriat R, Blanchet B, Durand JP, Boudou-Rouquette P, Michels J, et al. Sarcopenia predicts early dose-limiting toxicities and pharmacokinetics of sorafenib in patients with hepatocellular carcinoma. PLoS One 2012;7: e37563.42Yoshimura Y, Wakabayashi H, Yamada M, Kim H, Harada A, Arai H. Interventions for treating sarcopenia: a systematic review and meta-analysis of randomized controlled studies. J Am Med Dir Assoc 2017;18:553-.e1553.e16.43Michel JP. Sarcopenia: there is a need for some steps forward. J Am Med Dir Assoc 2014;15:379380.44Chen LK, Liu LK, Woo J, Assantachai P, Euyeung TW, Bahyah KS, et al. Sarcopenia in Asia: consensus report of the Asian Working Group for Sarcopenia. J Am Med Dir Assoc 2014;15:95101.45Naseeb MA, Volpe SL. Protein and exercise in the prevention of sarcopenia and aging. Nutr Res 2017;40:120.46Marzetti E, Calvani R, Tosato M, Cesari M, Di Bari M, Cherubini A, et al. Physical activity and exercise as countermeasures to physical frailty and sarcopenia. Aging Clin Exp Res 2017;29:3542.47Dirks ML, Tieland M, Verdijk LB, Losen M, Nilwik R, Mensink M, et al. Protein supplementation augments muscle fiber hypertrophy but does not modulate satellite cell content during prolonged resistance-type exercise training in frail elderly. J Am Med Dir Assoc 2017;18:608615.48Bauer JM, Verlaan S, Bautmans I, Brandt K, Donini LM, Maggio M, et al. Effects of a vitamin D and leucine-enriched whey protein nutritional supplement on measures of sarcopenia in older adults, the PROVIDE study: a randomized, double-blind, placebo-controlled trial. J Am Med Dir Assoc 2015;16:400411.49Bauer 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;14:542559.50Cruz-Jentoft AJ. Beta-hydroxy-beta-methyl butyrate (HMB): from experimental data to clinical evidence in sarcopenia. Curr Protein Pept Sci 2017; https://doi.org/10.2174/1389203718666170529105026. [Epub ahead of print].51Holeček M. Beta-hydroxy-beta-methylbutyrate supplementation and skeletal muscle in healthy and muscle-wasting conditions. J Cachexia Sarcopenia Muscle 2017; https://doi.org/10.1002/jcsm.12208. [Epub ahead of print].52Crame JT, Cruz-Jentoft AJ, Landi F, Hickson M, Zamboni M, Pereira SL, et al. Impacts of high-protein oral nutritional supplements among malnourished men and women with sarcopenia: a multicenter, randomized, double-blinded, controlled trial. J Am Med Dir Assoc 2016;17:10441055.53Morley JE. The mTOR conundrum: essential for muscle function, but dangerous for survival. J Am Med Dir Assoc 2016;17:963966.54Duque G, Daly RM, Sanders K, Kiel DP. Vitamin D, bones and muscle: myth versus reality. Australas J Ageing 2017;36:813.55Morley JE, Argiles JM, Evans WJ, Bhasin S, Cella D, Deutz NE, et al. Nutritional recommendations for the management of sarcopenia. J Am Med Dir Assoc 2009;10:591592.56Morley JE. Vitamin D redux. J Am Med Dir Assoc 2009;10:591592.57Anker SD, Morley JE, von Haehling S. Welcome to the ICD-10 code for sarcopenia. J Cachexia Sarcopenia Muscle 2016;7:512514.58Cao L, Morley JE. Sarcopenia is recognized as an independent condition by an international classification of disease, tenth revision, cinical modification (ICD-10-CM) code. J Am Med Dir Assoc 2016;17:675677.59Morley JE, Cao L. Rapid screening for sarcopenia. J Cachexia Sarcopenia Muscle 2015;6:312314.60Mijnarends DM, Schols JM, Meijers JM, Tan FE, Verlaan S, Luiking YC, et al. Instruments to assess sarcopenia and physical frailty in older people living in a community (care) setting: similarities and discrepancies. J Am Med Dir Assoc 2015;16:301308.61Heymsfield SB, Adamek M, Gonzalez MC, Jia G, Thomas DM. Assessing skeletal muscle mass: historical overview and state of the art. J Cachexia Sarcopenia Muscle 2014;5:918.62Hepple RT. Muscle atrophy is not always sarcopenia. J Appl Physiol (1985) 2012;113:677679.63Drey M, Krieger B, Sieber CC, Bauer JM, Hettwer S, Bertsch T, DISARCO study group. Motoneuron loss is associated with sarcopenia. J Am Med Dir Assoc 2014;15:435439.64Drey M, Behnes M, Kob R, Lepiorz D, Hettwer S, Bollheimer C, et al. C-terminal agrin fragment (CAF) reflects renal function in patients suffering from severe sepsis or septic shock. Clin Lab 2015;61:6976.65Rolland Y, Lauwers-Cances V, Cristini C, Abellan van Kan G, Janssen I, Morley JE, Vellas B. Difficulties with physical function associated with obesity, sarcopenia, and sarcopenic-obesity in community-dwelling elderly women: the EPIDOS (EPIDemiologie de l'OSteoporose) study. Am J Clin Nutr 2009;89:18951900.66Baumgartner RN, Wayne SJ, Waters DL, Janssen I, Gallagher D, Morley JE. Sarcopenia obesity predicts instrumental activities of daily living disability in the elderly. Obes Res 2004;12:19952004.67Morley JE. Sarcopenia in the elderly. Fam Pract 2012;29:i44i48.68Baumgartner RN, Waters DL, Gallagher D, Morley JE, Garry PJ. Predictors of skeletal muscle mass in elderly men and women. Mech Ageing Dev 1999;107:123136.69Rolland Y, Czerwinski S, Abellan van Kan G, Morley JE, Cesari M, Onder G, et al. Sarcopenia: its assessment, etiology, pathogenesis, consequences and future perspectives. J Nutr Health Aging 2008;12:433450.70Haren MT, Siddiqui AM, Armbrecht HJ, Kevorkian RT, Kim MJ, Haas MJ, et al. Testosterone modulates gene expression pathways regulating nutrient accumulation, glucose metabolism and protein turnover in mouse skeletal muscle. Int J Androl 2011;34:5568.71Bassil N, Morley JE. Late-life onset hypodonadism: a review. Clin Geriatr Med 2010;26:197222.72Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, et al. Testosterone trials investigators. N Engl J Med 2016;374:611624.73Samaras N, Samaras D, Frangos E, Forster A, Philippe J. A review of age-related dehydroepiandrosterone decline and its association with well-known geriatric syndromes: is treatment beneficial?
74Neto WK, Gama EF, Rocha LY, Ramos CC, Taets W, Scapini KB, et al. Effects of testosterone on lean mass gain in elderly men: systematic review with meta-analysis of controlled and randomized studies. Age (Dordr) 2015;37:9742.75Mirdamadi A, Garakyaraghi M, Pourmoghaddas A, Bahmani A, Mahmoudi H, Gharipour M. Beneficial effects of testosterone therapy on functional capacity, cardiovascular parameters, and quality of life in patients with congestive heart failure. Biomed Res Int 2014;2014:392432.76Stout M, Tew GA, Doll H, Zwierska I, Woodroofe N, Channer KS, Saxton JM. Testosterone therapy during exercise rehabilitation in male patients with chronic heart failure who have low testosterone status: a double-blind randomized controlled feasibility study. Am Heart J 2012;164:894901.77Toma M, McAlister FA, Coglianese EE, Vidi V, Vasaiwala S, Bakal JA, et al. Testosterone supplementation in heart failure: a meta-analysis. Circ Heart Fail 2012;5:315321.78Iellamo F, Volterrani 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 A Coll Cardiol 2010;56:13101316.79Caminiti 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;54:919927.80Malkin CJ, Channer KS, Jones TH. Testosterone and heart failure. Curr Opin Endocrinol Diabetes Obes 2010;17:262268.81Mason McClatchey P, Bauer TA, Regensteiner JG, Schauer IE, Huebschmann AG, Reusch JEB. Dissociation of local and global skeletal muscle oxygen transport metrics in type 2 diabetes. J Diabetes Complications 2017; https://doi.org/10.1016/j.jdiacomp.2017.05.004[Epub ahead of print].82Haas TL, Nwadozi E. Regulation of skeletal muscle capillary growth in exercise and disease. Appl Physiol Nutr Metab 2015;40:12211232.83Porter TR. Detecting skeletal microvascular flow abnormalities in diabetes: could microvascular recruitment be a fundamental problem? JACC Cardiovasc Imaging 2015;8:922923.84Heinonen I, Koga S, Kalliokoski KK, Musch TI, Poole DC. Heterogeneity of muscle blood flow and metabolism: influence of exercise, aging, and disease states. Exerc Sport Sci Rev 2015;43:117124.85Morley JE, Baumgartner RN. Cytokine-related aging process. J Gerontol A Biol Sci Med Sci 2004;59:M924M929.86Bano G, Trevisan C, Carraro S, Solmi M, Luchini C, Stubbs B, et al. Inflammation and sarcopenia: a systematic review and meta-analysis. Maturitas 2017;96:1015.87Sakuma K, Aoi W, Yamaguchi A. Molecular mechanisms of sarcopenia and cachexia: recent research advances. Pflugers Arch 2017;469:573591.88Han HQ, Zhou X, Mitch WE, Goldberg AL. Myostatin/activin pathway antagonism: molecular basis and therapeutic potential. Int J Biochem Cell Biol 2013;45:23332347.89McKay BR, Ogborn DI, Bellamy LM, Ternopolsky MA, Parise G. Myostatin is associated with age-related human muscle stem cell dysfunction. FASEB J 2012;26:25092521.90Ju CR, Chen RC. Serum myostatin levels and skeletal muscle wasting in chornic obstructive pulmonary disease. Respir Med 2012;106:102108.91Becker C, Lord SR, Studenski SA, Warden SJ, Fielding RA, Recknor CP, et al. Myostatin antibody (LY2495655) in older weak fallers: a proof-of-concept, randomised, phase 2 trial. Lancet Diabetes Endocrinol 2015;3:948957.92Rooks D, Praestgaard J, Hariry S, Laurent D, Petricoul O, Perry RG, et al. Treatment of sarcopenia with bimagrumab: results from a phase II, randomized, controlled, proof-of-concept study. J Am Geriatr Soc 2017; https://doi.org/10.1111/jgs.14927[Epub ahead of print].93Attie KM, Borgstein 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;47:416423.94Seo J, Chu H, Lee JS, Kim DY. Mucocutaneous telangiectasia as a diagnostic clue of hereditary hemorrhagic telangiectasia: an activing receptor-like Kinase-1 mutation inaKorean patient. Ann Dermatol 2016;28:264266.95Alaa El Din F, Patri S, Thoreau V, Rodriguez-Ballesteros M, Hamade E, Bailly S, et al. Functional and splicing defect analysis of 23 ACVRL1 mutations in a cohort of patients affected by hereditary hemorrhagic telangiectasia. PLoS One 2015;10: e0132111.96Gonzalez-Montalvo JI, Alarcon T, Gotor P, Queipo R, Velasco R, Hoyoys R, et al. Prevalence of sarcopenia in acute hip fracture patients and its influence on short-term clinical outcome. Geriatr Gerontol Int 2016;16:10211027.97Guo R, Wan Y, Xu D, Cui L, Deng M, Zhang G, et al. Generation and evaluation of myostatin knock-out rabbits and goats using CRISPR/Cas9 system. Sci Rep 2016;https://doi.org/10.1038/srep29855.
98Bouchard C, Antunes-Correa LM, Ashley EA, Franklin N, Hwang PM, Mattsson CM, et al. Personalized preventive medicine: genetics and the response to regular exercise in preventive interventions. Prog Cardiovasc Dis 2015;57:337346.99Churchward-Venne TA, Tieland M, Verdijk LB, Leenders M, Dirks ML, de Groot LC, van Loon LJ. There are no nonresponders to resistance-type exercise training in older men and women. J Am Med Dir Assoc 2015;16:400411.100Dutton GR, Lewis CE. The look AHEAD trial: implications for lifestyle intervention in type 2 diabetes mellitus. Prog Cardiovasc Dis 2015;58:6975.101Argiles JM, Anker SD, Evans WJ, Morley JE, Fearon KC, Strasser F, et al. Consensus on cachexia definitions. J Am Med Dir Assoc 2010;11:229230.102Onesti JK, Guttridge DC. Inflammation based regulation of cancer cachexia.
103Ezeoke CC, Morley JE. Pathophysiology of anorexia in the cancer cachexia syndrome. J Cachexia Sarcopenia Muscle 2015;6:287302.104Hahn AW, Gill DM, Pal SK, Agarwal N. The future of immune checkpoint cancer therapy after PD-1 and CTLA-4. Immunotherapy 2017;9:681692.105Kortebein P, Ferrando A, Lombeida J, Wolfe R, Evans WJ. Effect of 10 days of bed rest on skeletal muscle in healthy older adults. JAMA 2007;297:17721774.106Kress JP, Hall JB. ICU-acquired weakness and recovery from critical illness. N Engl J Med 2014;370:16261635.107Schweickert WD, Kress JP. Implementing early mobilization interventions in mechanically ventilated patients in the ICU. Chest 2011;140:16121617.108von Haehling S, Morley JE, Coats AJS, Anker SD. Ethical guidelines for publishing in the Journal of Cachexia, Sarcopenia and Muscle: update 2015. J Cachexia Sarcopenia Muscle 2015;6:315316.