Sarcopenia – Endocrinological and Neurological Aspects

Abstract

Sarcopenia in geriatric patients is often associated with or even caused by changes of the endocrine and nervous system. The multifactorial pathogenesis of sarcopenia and additional multimorbidity in geriatric patients makes it difficult to study distinct pathogenic pathways leading to sarcopenia. Patients suffering from diabetes, Cushing’s syndrome, chronic kidney disease, Klinefelter’s syndrome or motor neuron diseases, such as amyotrophic lateral sclerosis for example are known to have impaired muscle property and reduced physical performance. These patients are typically younger and suffer from conditions caused by a known molecular disease mechanism and a peculiar sarcopenic phenotype. Therefore, these sequelae can serve as prototypic disease models to study isolated endocrinological and neurodegenerative causes for sarcopenia. This review focuses on diseases whose etiopathogenesis of muscle impairment is known. The idea is to use these diseases as proof of principles to develop a classification algorithm of sarcopenia in the elderly to make a more mechanism-oriented therapy be possible.

Key words

sarcopenia - pathomechanisms - muscle - hormones - diabetes - neurodegeneration

• Literature

• 1 Cruz-Jentoft AJ, Baeyens JP, Bauer JM. et al. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing 2010; 39: 412-423
• 2 Rosenberg I. Summary comments: Epidemiological and methodological problems in determining nutritional status of older persons. Am J Clin Nutr 1987; 50: 1231-2133
• 3 Morley JE, Abbatecola AM, Argiles JM. et al. Sarcopenia with limited mobility: An international consensus. J Am Med Dir Assoc 2011; 12: 403-409
• 4 Malmstrom TK, Miller DK, Simonsick EM. et al. SARC-F: A symptom score to predict persons with sarcopenia at risk for poor functional outcomes. J Cachexia Sarcopenia Muscle 2016; 7: 28-36
• 5 Woo J, Leung J, Morley JE. Validating the SARC-F: A suitable community screening tool for sarcopenia?. J Am Med Dir Assoc 2014; 15: 630-634
• 6 Morley JE. Pharmacologic Options for the Treatment of Sarcopenia. Calcif Tissue Int. Springer US 2016; 98: 319-333
• 7 Morley JE, Argiles JM, Evans WJ. et al. Nutritional recommendations for the management of sarcopenia. J Am Med Dir Assoc 2010; p 391-396
• 8 Anker SD, Morley JE, von Haehling S. Welcome to the ICD-10 code for sarcopenia. J Cachexia Sarcopenia Muscle 2016; 7: 512-514
• 9 Koo BK, Roh E, Yang YS. et al. Difference between old and young adults in contribution of β-cell function and sarcopenia in developing diabetes mellitus. J Diabetes Investig 2016; 7: 233-240
• 10 Kalyani RR, Corriere M, Ferrucci L. Age-related and disease-related muscle loss: The effect of diabetes, obesity, and other diseases. Lancet Diabetes Endocrinol 2014; 2: 819-829
• 11 Dimitriadis G, Mitrou P, Lambadiari V. et al. Insulin effects in muscle and adipose tissue. Diabetes Res Clin Pract 2011; 93: S52-S59
• 12 Cartee GD, Funai K. Exercise and insulin: Convergence or divergence at AS160 and TBC1D1?. Exerc Sport Sci Rev 2009; 188-195
• 13 Schiaffino S, Dyar KA, Ciciliot S. et al. Mechanisms regulating skeletal muscle growth and atrophy. FEBS J 2013; 280: 4294-4314
• 14 Cleasby ME, Jamieson PM, Atherton PJ. Insulin resistance and sarcopenia: Mechanistic links between common co-morbidities. J Endocrinol 2016; 229: R67-R81
• 15 Cuthbertson DJ, Babraj J, Leese G. et al. Anabolic resistance does not explain sarcopenia in patients with type 2 diabetes mellitus, compared with healthy controls, despite reduced mTOR pathway activity. Clin Nutr. Elsevier Ltd 2016; 10-13
• 16 Lawrence JC. mTOR-dependent control of skeletal muscle protein synthesis. Int J Sport Nutr Exerc Metab 2001; 11 Suppl S177-S185
• 17 Bouchi R, Fukuda T, Takeuchi T. et al. Insulin Treatment Attenuates Decline of Muscle Mass in Japanese Patients with Type 2 Diabetes. Calcif Tissue Int. Springer US 2017; 0: 1-8
• 18 Cetrone M, Mele A, Tricarico D. Effects of the antidiabetic drugs on the age-related atrophy and sarcopenia associated with diabetes type II. Curr Diabetes Rev 2014; 10: 231-237
• 19 Rasmussen BB, Fujita S, Wolfe RR. et al. Insulin resistance of muscle protein metabolism in aging. FASEB J. 2006; 20: 768-769
• 20 Fujita S, Glynn EL, Timmerman KL. et al. Supraphysiological hyperinsulinaemia is necessary to stimulate skeletal muscle protein anabolism in older adults: Evidence of a true age-related insulin resistance of muscle protein metabolism.. Diabetologia 2009; 52: 1889-1898
• 21 Wang X, Hu Z, Hu J. et al. Insulin resistance accelerates muscle protein degradation: Activation of the ubiquitin-proteasome pathway by defects in muscle cell signaling. Endocrinology. 2006; 147: 4160-4168
• 22 Shea MK, Nicklas BJ, Marsh AP. et al. The effect of pioglitazone and resistance training on body composition in older men and women undergoing hypocaloric weight loss. Obesity (Silver Spring) 2011; 19: 1636-1646
• 23 Zhou G, Myers R, Li Y. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001; 108: 1167-1174
• 24 Koh HJ, Brandauer J, Goodyear LJ. LKB1 and AMPK and the regulation of skeletal muscle metabolism. Curr Opin Clin Nutr Metab Care 2008; 11: 227-232
• 25 Herzig S, Shaw RJ. AMPK: Guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol. 2018; 121-135
• 26 Bujak AL, Crane JD, Lally JS. et al. AMPK activation of muscle autophagy prevents fasting-induced hypoglycemia and myopathy during aging. Cell Metab. 2015; 21: 883-890
• 27 Thomson DM, Gordon SE. Diminished overload-induced hypertrophy in aged fast-twitch skeletal muscle is associated with AMPK hyperphosphorylation. J Appl Physiol 2005; 98: 557-564
• 28 Bolster DR, Crozier SJ, Kimball SR. et al. AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling. J Biol Chem 2002; 277: 23977-23980
• 29 Shan T, Zhang P, Liang X. et al. Lkb1 is indispensable for skeletal muscle development, regeneration, and satellite cell homeostasis. Stem Cells. 2014; 32: 2893-2907
• 30 Zhang C, McFarlane C, Lokireddy S. et al. Myostatin-deficient mice exhibit reduced insulin resistance through activating the AMP-activated protein kinase signalling pathway. Diabetologia 2011; 54: 1491-1501
• 31 Das AK, Yang QY, Fu X. et al. AMP-activated protein kinase stimulates myostatin expression in C2C12 cells. Biochem Biophys Res Commun 2012; 427: 36-40
• 32 Sumantri S, Setiati S, Purnamasari D. et al. Relationship between metformin and frailty syndrome in elderly people with type 2 diabetes. Acta Med Indones 2014; 46: 183-188
• 33 Laksmi PW, Setiati S, Tamin TZ. et al. Effect of metformin on handgrip strength, gait speed, myostatin serum level, and health-related quality of life: A double blind randomized controlled trial among non-diabetic pre-frail elderly patients. Acta Med Indones 2017; 49: 118-127
• 34 Buteau J. GLP-1 receptor signaling: Effects on pancreatic beta-cell proliferation and survival. Diabetes Metab 2008; 34 (Suppl. 02) S73-S77
• 35 Nyström T. The potential beneficial role of glucagon-like peptide-1 in endothelial dysfunction and heart failure associated with insulin resistance. Horm Metab Res 2008; 40: 593-606
• 36 Chai W, Dong Z, Wang N. et al. Glucagon-like peptide 1 recruits microvasculature and increases glucose use in muscle via a nitric oxide-dependent mechanism. Diabetes 2012; 61: 888-896
• 37 Perna S, Guido D, Bologna C. et al. Liraglutide and obesity in elderly: Efficacy in fat loss and safety in order to prevent sarcopenia. A perspective case series study. Aging Clin Exp Res 2016; 28: 1251-1257
• 38 Giannocco G, Oliveira KC, Crajoinas RO. et al. Dipeptidyl peptidase IV inhibition upregulates GLUT4 translocation and expression in heart and skeletal muscle of spontaneously hypertensive rats. Eur J Pharmacol 2013; 698: 74-86
• 39 Bouchi R, Fukuda T, Takeuchi T et al. Dipeptidyl peptidase 4 inhibitors attenuates the decline of skeletal muscle mass in patients with type 2 diabetes. Diabetes Metab Res Rev 2017
• 40 Merovci A, Solis-Herrera C, Daniele G. et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest 2014; 124: 509-514
• 41 Sugiyama S, Jinnouchi H, Kurinami N. et al. Dapagliflozin reduces fat mass without affecting muscle mass in type 2 diabetes. J Atheroscler Thromb 2017; 25: 467-476
• 42 Fujita S, Rasmussen BB, Cadenas JG. et al. Aerobic exercise overcomes the age-related insulin resistance of muscle protein metabolism by improving endothelial function and akt / mammalian target of rapamycin signaling. Diabetes 2007; 56: 1615-1622
• 43 Verreijen aM, Engberink MF, Verlaan S. et al Op019 exploration of what level of protein is needed for muscle mass accretion during weight loss with resistance training in obese elderly. Clin Nutr 2013; 32: S8
• 44 Berr CM, Stieg MR, Deutschbein T. et al Persistence of myopathy in Cushing’s syndrome: Evaluation of the German Cushing’s Registry. Eur J Endocrinol 2017; 176: 737-746
• 45 Drey M, Berr CM, Reincke M. et al. Cushing’s syndrome: A model for sarcopenic obesity. Endocrine 2017; 57: 481-485
• 46 Kang S-H, Lee H-A, Kim M. et al Forkhead box O3 plays a role in skeletal muscle atrophy through expression of E3 ubiquitin ligases MuRF-1 and atrogin-1 in Cushing’s syndrome. Am J Physiol - Endocrinol Metab 2017; 312: E495-E507
• 47 Zhao W, Qin W, Pan J. et al. Dependence of dexamethasone-induced Akt/FOXO1 signaling, upregulation of MAFbx, and protein catabolism upon the glucocorticoid receptor. Biochem Biophys Res Commun. Elsevier Inc 2009; 378: 668-672
• 48 Clarke BA, Drujan D, Willis MS. et al. The E3 ligase MuRF1 degrades myosin heavy chain protein in dexamethasone-treated skeletal muscle. Cell Metab 2007; 6: 376-385
• 49 Mammucari C, Milan G, Romanello V. et al. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab 2007; 6: 458-471
• 50 Baumgartner RN. Body composition in healthy aging. Ann N Y Acad Sci 2000; 904: 437-448
• 51 Waters DL, Baumgartner RN, Garry PJ. Advantages of dietary, exercise-related, and therapeutic interventions to prevent and treat sarcopenia in adult patients: An update. Clin Interv Aging 2010; 259-270
• 52 Mazziotti G, Chiavistelli S, Giustina A. Pituitary diseases and bone. Endocrinol Metab Clin North Am 2015; 44: 171-180
• 53 Ormsbee MJ, Prado CM, Ilich JZ. et al. Osteosarcopenic obesity: the role of bone, muscle, and fat on health. J Cachexia Sarcopenia Muscle 2014; 5: 183-192
• 54 Bolanowski M, Halupczok J, Jawiarczyk-Przybyłowska A. Pituitary disorders and osteoporosis. Int J Endocrinol 2015; DOI: 10.1155/2015/206853.
• 55 Doak CM, Wijnhoven TMA, Schokker DF. et al. Age standardization in mapping adult overweight and obesity trends in the WHO European Region. Obes Rev 2012; 174-191
• 56 Fahal IH. Uraemic sarcopenia: Aetiology and implications. Nephrol Dial Transplant 2014; 29: 1655-1665
• 57 Epstein FH, Mitch WE, Goldberg AL. Mechanisms of muscle wasting — the role of the ubiquitin–proteasome pathway. N Engl J Med 1996; 335: 1897-1905
• 58 Kaizu Y, Ohkawa S, Odamaki M. et al. Association between inflammatory mediators and muscle mass in long-term hemodialysis patients. Am J Kidney Dis 2003; 42: 295-302
• 59 Sato E, Mori T, Mishima E. et al. Metabolic alterations by indoxyl sulfate in skeletal muscle induce uremic sarcopenia in chronic kidney disease. Sci Rep 2016; 6: 36618
• 60 Song YH, Li Y, Du J. et al. Muscle-specific expression of IGF-1 blocks angiotensin II-induced skeletal muscle wasting. J Clin Invest 2005; 115: 451-458
• 61 Delafontaine P, Yoshida T. The renin-angiotensin system and the biology of skeletal muscle: Mechanisms of muscle wasting in chronic disease states. Trans Am Clin Climatol Assoc 2016; 127: 245-258
• 62 Montano-Loza AJ, Angulo P, Meza-Junco J et al. Sarcopenic obesity and myosteatosis are associated with higher mortality in patients with cirrhosis. J Cachexia Sarcopenia Muscle 2015; 6: 126–135
• 63 Stumvoll M, Meyer C, Mitrakou A. et al. Important role of the kidney in human carbohydrate metabolism. Med Hypotheses 1999; 52: 363-366
• 64 Wang XH, Du J, Klein JD. et al. Exercise ameliorates chronic kidney disease-induced defects in muscle protein metabolism and progenitor cell function. Kidney Int 2009; 76: 751-759
• 65 Caballero PEJ. Klinefelter’s syndrome associated with progressive muscular atrophy simulating Kennedy’s disease. Ann Indian Acad Neurol 2012; 15: 227-229
• 66 Bardsley MZ, Falkner B, Kowal K. et al. Insulin resistance and metabolic syndrome in prepubertal boys with Klinefelter syndrome. Acta Paediatr 2011; 100: 866-870
• 67 Basualto-Alarcón C, Varela D, Duran J et al. Sarcopenia and androgens: A link between pathology and treatment. Front Endocrinol (Lausanne) 2014; 5: 217
• 68 Perry HM, Horowitz M, Morley JE. et al. Longitudinal changes in serum 25-hydroxyvitamin D in older people. Metabolism 1999; 48: 1028-1032
• 69 Feldman HA, Longcope C, Derby CA. et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: Longitudinal results from the Massachusetts Male Aging Study. J Clin Endocrinol Metab 2002; 87: 589-598
• 70 Nieschlag E. Current topics in testosterone replacement of hypogonadal men. Best Pract Res Clin Endocrinol Metab 2015; 29: 77-90
• 71 Frisoli A, Chaves PHM, Pinheiro MM. et al. The effect of nandrolone decanoate on bone mineral density, muscle mass, and hemoglobin levels in elderly women with osteoporosis: A double-blind, randomized, placebo-controlled clinical trial.. J Gerontol A Biol Sci Med Sci 2005; 60: 648-653
• 72 Chiò A, Logroscino G, Traynor BJ. et al. Global epidemiology of amyotrophic lateral sclerosis: A systematic review of the published literature. Neuroepidemiology 2013; 41: 118-130
• 73 Haverkamp LJ, Appel V, Appel SH. Natural history of amyotrophic lateral sclerosis in a database population. Validation of a scoring system and a model for survival prediction. Brain 1995; 118 Pt 3 707-719
• 74 Chia R, Chiò A, Traynor BJ. Novel genes associated with amyotrophic lateral sclerosis: Diagnostic and clinical implications. Lancet Neurol 2018; 17: 91-102
• 75 Cappello V, Francolini M. Neuromuscular junction dismantling in amyotrophic lateral sclerosis. Int J Mol Sci 2017; DOI: 10.3390/ijms18102092.
• 76 Moloney EB, de Winter F, Verhaagen J. ALS as a distal axonopathy: Molecular mechanisms affecting neuromuscular junction stability in the presymptomatic stages of the disease. Front Neurosci 2014; 8: 252
• 77 Uitti RJ, Berry K, Yasuhara O. et al. Neurodegenerative ‘overlap’ syndrome: Clinical and pathological features of Parkinson’s disease, motor neuron disease, and Alzheimer’s disease. Parkinsonism Relat Disord 1995; 1: 21-34
• 78 Drey M, Hasmann SE, Krenovsky J-P. et al. Associations between Early Markers of Parkinson’s Disease and Sarcopenia. Front Aging Neurosci 2017; 9: 53
• 79 Bromberg MB. MUNIX and MUNE in ALS. Clin Neurophysiol. 2013; 124: 433-434
• 80 McComas AJ, Fawcett PR, Campbell MJ. et al. Electrophysiological estimation of the number of motor units within a human muscle. J Neurol Neurosurg Psychiatry 1971; 34: 121-131
• 81 Nandedkar SD, Nandedkar DS, Barkhaus PE. et al. Motor unit number index (MUNIX). IEEE Trans Biomed Eng 2004; 51: 2209-2211
• 82 Neuwirth C, Nandedkar S, Stålberg E. et al. Motor Unit Number Index (MUNIX): A novel neurophysiological marker for neuromuscular disorders; test-retest reliability in healthy volunteers. Clin Neurophysiol. International Federation of Clinical Neurophysiology 2011; 122: 1867-1872
• 83 Nandedkar SD, Barkhaus PE, Stålberg EV. Reproducibility of MUNIX in patients with amyotrophic lateral sclerosis. Muscle Nerve. 2011; 44: 919-922
• 84 Drey M, Grösch C, Neuwirth C. et al. The Motor Unit Number Index (MUNIX) in sarcopenic patients. Exp Gerontol 2013; 48: 381-384
• 85 Drey M, Krieger B, Sieber CC. et al. Motoneuron loss is associated with sarcopenia. J Am Med Dir Assoc 2014; 15: 435-439
• 86 Rudolf R, Deschenes MR, Sandri M. Neuromuscular junction degeneration in muscle wasting. Curr Opin Clin Nutr Metab Care 2016; 19: 177-181
• 87 Stephan A, Mateos JM, Kozlov SV. et al. Neurotrypsin cleaves agrin locally at the synapse. FASEB J 2008; 22: 1861-1873
• 88 Drey M, Sieber CC, Bauer JM. et al. C-terminal Agrin Fragment as a potential marker for sarcopenia caused by degeneration of the neuromuscular junction. Exp Gerontol 2013; 48: 76-80
• 89 Hettwer S, Lin S, Kucsera S. et al. Injection of a soluble fragment of neural agrin (NT-1654) considerably improves the muscle pathology caused by the disassembly of the neuromuscular junction. PLoS One 2014; 9: e88739
• 90 Heymsfield SB, Adamek M, Gonzalez MC. et al. Assessing skeletal muscle mass: Historical overview and state of the art. J Cachexia Sarcopenia Muscle 2014; 9-18
• 91 Scharf G, Heineke J. Finding good biomarkers for sarcopenia. J Cachexia Sarcopenia Muscle 2012; 3: 145-148
• 92 Ebner N, Steinbeck L, Doehner W. et al. Highlights from the 7th Cachexia Conference: Muscle wasting pathophysiological detection and novel treatment strategies. J Cachexia Sarcopenia Muscle 2014; 5: 27-34
• 93 Drescher C, Konishi M, Ebner N. et al. Loss of muscle mass: Current developments in cachexia and sarcopenia focused on biomarkers and treatment. Int J Cardiol 2016; 202: 766-772
• 94 Arnold AS, Egger A, Handschin C. PGC-1α and myokines in the aging muscle – A mini-review. Gerontology 2010; 37-43
• 95 Inui A. Cancer anorexia-cachexia syndrome: Current issues in research and management. CA Cancer J Clin 2002; 52: 72-91
• 96 Morley JE, Kaiser FE, Perry HM. et al. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism 1997; 46: 410-413
• 97 Morley JE. Scientific overview of hormone treatment used for rejuvenation. Fertil Steril 2013; 1807-1813
• 98 Kovacheva EL, Sinha Hikim AP. et al. Testosterone supplementation reverses sarcopenia in aging through regulation of myostatin, c-Jun NH2-terminal kinase, Notch, and Akt signaling pathways. Endocrinology. 2010; 151: 628-638
• 99 Crawford JC, Johnston MA, Hancock ML. et al. Enobosarm, a selective androgen receptor modulator (SARM), increases lean bodymass (LBM) in advanced nsclc patients; updated results of two pivotal, international phase 3 trials. Support care cancer 2014; 22: S30-S31