Sarcopenia, as defined by the EWSOG, is a skeletal muscle condition attributed to age in which there is significant muscle atrophy, loss of mass, strength and functional capacity (1). Cachexia , by comparison is a metabolic condition arising from severe injury or disease , often appearing at the end-stage of malignant infection with accentuated muscle atrophy .Sarcopenia is often cited as a geriatric disease , its mechanism of cause poorly elucidated , yet treatment widely available .Cachexia is by contrast , disease-induced inflammation with limited treatment options .The conditions result in Type II oxidative fibre degeneration , fibrosis and conversion to fast twitch fibres , with loss of muscle protein required for skeletal muscle function .Sarcopenia develops from imbalances in protein synthesis and degradation with denervation and fibre changes catalysed by hormonal and pro-inflammatory changes inhibiting myofibril repair .Cachexia is driven by inflammation , which actively promotes abnormal proteolysis, aided by a compromised host .Both are complicated by additional factors , obesity and insulin resistance in the elderly , anorexia and poor nutrition in diseased patients . The conditions provide a continuous working challenge in the clinical setting, thus counteracting their effects on quality of life, mortality and morbidity and general health remain key focal points in current research.
Pathophysiology of Sarcopenia and Cachexia:
Myogenesis or skeletal muscle synthesis is a tightly regulated cascade, centred on the Akt - Protein Kinase B signalling pathway. In sarcopenia there is disproportion in protein synthesis with protein catabolism, in cachexia is synthesis is abrogated with the negative effectors overwhelming the Akt pathway, driving degradation.
Aging induces the morphological changes that characterises sarcopenia, denervation and loss of complete motor units, fibrosis of tissue and conversion to glycolytic fibres. Hormonal changes have notable impacts in accelerating this development. Myostatin, glucocorticoids and more recently angiotensin, TGFβ receptor ligands, have been indicted in this age-prone imbalance. Myostatin, a potent inhibitor of skeletal muscle proliferation is overexpressed in advancing age (2). It promotes cessation of satellite cell proliferation through its TGFb receptor-ActRiia (3). Its binding recruits R-Smad 2/3 and co-Smad 4, which oligomerise, translocate to the nucleus, preventing up-regulation of muscle regulatory factors and myocyte enhancer factor 2 (4). Myogenic factors including Pax7 and MyoD are blocked, thereby stalling differentiation into the myocyte cell lineage (2).R-Smads, at high concentrations can inhibit Akt, mTOR and thus p70S6k, which normally mutes FOXo-3 and E3 ligase MuRF1 (4) . Degradation is therefore promoted via the ubiquitin-proteasome system (UPS), one of the four principal proteolytic pathways(5). Angiotensin II also operates through UPS via increasing IL-6 and glucocorticoid concentrations thereby antagonising insulin and protein synthesis .Anabolic hormones including GH and IGF-1 are diminished with aging , Growth Hormone stimulates hepatocyte release of IGF-1 (insulin-like growth factor) for muscle metabolism. IGF-1 is also sourced from exercised skeletal muscle .
Pathophysiology of Sarcopenia and Cachexia:
IGF-1 stimulates proliferation, via the phosphatidyl-inositol 3 kinase -Akt pathway .Aging reduces muscular IGF-1 release , thus replacement of muscle protein declines with myostatin inhibiting IGF-1 function .
With sarcopenia, the muscle synthesis-degradation equation is imbalanced .Degradation is guided by UPS, Ca2+and caspase dependent and lysosomal pathways .UPS is both non-selective in protein degradation and most active in sarcopenic muscle. Its activated through pro-inflammatories including NFκB and TNFα , which increase in aging circulation (3) .NFκB activates UPS through E3 ligase MURF1 up-regulation. TNFα and reactive oxygen species (ROS) stimulate NFkB through deactivation of IκBα, inhibitor of NFκB release. Prolongation of NFκb thus has deleterious effects including metabolic conversion to glycolysis and muscle degradation (6),(7) .Mitochondrial biogenesis bears muscle insult also , enhanced ROS from aging energy complexes and reduced antioxidant function allow interaction with NFkB ,lipid peroxidation and cellular insult leading to caspase-induce apoptosis
Cachexia as an atrophic condition originates from systemic inflammation provoked by diseases such as COPD, cancer and cardiovascular injury .Inflammation induces aberrant control of metabolism , skeletal muscle maintains a key position in energy balance , thus emerging as a victim of inflammation's effect .The U-P system and autophagy , proteolytic pathways , become central to muscle atrophy observed in patients of cachexia .Autophagy enables removal of damaged organelles and long lived proteins , a similar function of UPS. Both pathways are up-regulated through p38 α/β MAPK , which can be activated through oxidative stress derived from ROS activity . Elevated Nitric Oxide levels are observed in cachexia as a result of elevated NO synthase expression , guided by TNF-α and interferon .TNF-α , a pleiotropic cytokine is heavily involved the proteolytic pathways .Tumor necrosis factor-α enhances its own mRNA expression thereby increasing plasma levels . Through this , NFκB expression increases , raising UPS activity and myofibril protein degradation .Chemotaxis through TNF effect on endothelial cell of local blood vessels , attracts resident neutrophils and macrophages . There is further TNF release as well other inflammatory modulators that antagonise muscle growth and energy creation .IL-6 is a leading example , a potent inhibitor of insulin , IL-6
Consequences of Muscle Loss:
Conspicuous reductions in muscle mass pose a host of challenges to the body including reductions in muscle strength and endurance, decreased insulin action and others .With large muscle mass reduction there is a clinical decrease in the lean body mass index, which is loosely measured around fat-free soft tissue . Decrease in mass is accompanied by a reduction in endurance, derived from elevated fast-twitch glycolytic muscle fibres. Individuals with such muscle loss may present with fatigue, rapid production of lactic acid , and muscle ache , given muscle oxidative capacity has been removed .In elderly patients particularly , there is diminished functional capacity and strength (8).Insulin function is also impacted ; insulin regulates metabolic function in skeletal muscle , thus diminished muscle provides a lesser site for insulin effect .This may as some research indicates , a predisposition to Type II diabetes , if not temporarily .If blood samples are taken , as in a clinical diagnosis setting , glucose levels may be raised .The liver produces glucose via gluconeogenesis , given protein turnover is attenuated with declining muscle , these liberated amino acids are thus harnessed for energy production (9).
Combined with this is rapid increase in fatty acid deposition as adipose tissue, muscle capacity for fatty acid oxidation is also invoked when Type II oxidative fibres are lost. Serum levels of fatty acids are therefore elevated and diverted to where it may be stored. Histologically, muscle may be invested with fatty streaks, a consequence of incapacity for β-oxidation .
Diagnostics and Treatment:
Sarcopenia, under the EWGSOP conference in Rome, 2009, has been addressed clinically in relation to diagnosis and treatment, with assessments and criteria to structure the condition while addressing its materialisation in patients (1). Cachexia, on the other hand remains less structured in relation to diagnosis and treatment, primarily based on the complexities of the underlying disease, patient condition and thus clinical research into adequate treatment and prevention.
Sarcopenia, under the EWGSOP, was both addressed, in relation to its definition and the translation of this into patient diagnosis, analysis and hence treatment .Criteria developed stem from this definition, reduced muscle mass with either low muscle strength or physical performance, notably in age related patient. Staging reflects the criteria, based on the severity of the condition; pre-sarcopenia, sarcopenia and severe sarcopenia, each varying in muscle morphology and properties. Assessment is orientated around these criteria, quantifying the severity through individual examinations. Muscle mass measurements include body imaging techniques , total potassium per fat-free soft tissue and bio-impedance analysis .Body imaging techniques are comprised of MRI and CT , for segmental and total body mass , BIA or bioelectric impedance analysis is used at the molecular level for lean tissue and fat volume , while DEXA - dual energy X absorptiometry is an advanced correlate of MRI and CT .Muscle strength assessment includes handgrip strength reflecting lower extremity muscle power and knee extension torque , thus poor results clinically imply poor capacity . Knee flexion and extension is also assessed through isometric and isokinetic means, reduced mobility here is associated with sarcopenic-induced power loss in the lower extremities .Physical performance in conclusion includes test batteries such as Short Physical Performance Battery, usual gait speed and timed-'get-up-and-go' test. Although rigorous, these physical tests provide clear clinical information and thus a firm basis to diagnosis sarcopenia as present or not (1).
Diagnostic criteria remain quite loose in relation to diagnosis of cachexia, patient condition often being a factor in limiting the diagnostic evaluation. It is generally accepted that the muscle constant lies around the fifth percentile for middle age adults , thus changes in BMI , weight , albumin content and cytokines tends towards cachexia . Weight loss , a BMI <20 in those aged <65yrs or BMI <22 in those > 65yrs . , albumin content less than 35g /L and increased cytokine levels precipitate towards cachexia .There is much discordance in diagnosing cachexia in those with cancer , as a 5% weight reduction may not be deemed significant . However criteria for cachexia encompass those assigned to sarcopenia, with anorexia or limited food intake, low fat-free mass index and abnormal biochemistry(10).
Treatment of sarcopenia and cachexia comprise both non-pharmacological and pharmacological regimens, however the latter proves more complex arising from the cachexia type and advancement of the underlying disease condition(11).
Physical resistance exercise has been shown as non-pharmacological regimen in attenuating sarcopenia .Its involvement as treatment has revealed results, improvements in muscle strength and mass; however the indication is of exercise in poorly compliant elderly patients (12) .
Diagnostics and Treatment:
Pharmacological treatment of sarcopenia is a major area of research. Many drugs including the ghrelin seratagogue and the myostatin inhibitor have yielded potentiality however they bore little impact on restoration of functional capacity or muscle contraction. Testosterone and Growth Hormone attenuate fatty masses that develop often in sarcopenia from adipocyte growth intramuscularly; however the side-effects are severe, aggressive and violent tendencies, stimulation of tumour growth and vague understanding of efficacy and system interactions. DHA (docosahexanoic acid) and Vitamin D yielded some positive results, DHA's effect more dubious. Vitamin D proved to have less indications and side-effects, through acting on its Vitamin D receptor in skeletal muscle to initiate protein synthesis (13).
The ω-3 fatty acid EPA - eicosapentaenoic acid has been shown to have anti-cachectic and anti-tumour effects in a research setting, EPA blocking the PIF, proteolysis inducing factor, thereby attenuating cachexia in patients. Clinical trials have however yielded ambivalent results , with much deliberation upon the adequate dosage and thus EPA functioning in the PIF induced pathway .ACE inhibitors , used for primary and secondary prevention of cardiovascular disease , have become recognised in their interaction with skeletal muscle. ACEis have been shown to elevate IGF-1 levels and mitochondrial numbers combined with increased angiogenesis of endothelial cells .Improvements in lean muscle mass and lesser muscle strength decline have also been observed in those treated with ACE inhibitors .Although there is a lack of a large body evidence for ACEis in sarcopenia, their prescription to those with hypertension provides some of the anti-sarcopenic effects outlined.
Cachexia remains a complex condition to treat, with treatment being largely focused on nutrition and pharmacological intervention where possible .The ESPN -European society for palliative nutrition and EAPRC- European Palliative Care Research Collaborative recommend enteral nutrition, nasogastric, nasoenteral or percutaneous tube feeding for patients losing weight due to insufficient intake. Parenteral nutrition is less inclined in those with cachexia, especially those with cancer, given the poor nutrition state and threat of infection. Supplementation with EPA, proteins, minerals and others may provide some attenuation of weight loss; again the clinical findings are confounded. .EPA was shown in cachectic murine models to attenuate the weight loss effects however human patient's responses have not been successful due to patient inability to precede. However it is recommended to be incorporated into a multi- therapy treatment .Physical therapy indicted as being beneficial due to increased insulin sensitivity, protein synthesis and anti-oxidant enzymes.
Drug therapy is indicated as treatment; nevertheless evidence defining treatment has yet to be acquired in clinical trials. The ω-3 fatty acid EPA - eicosapentaenoic acid has been shown to have anti-cachectic and anti-tumour effects in a research setting, EPA blocking the PIF, proteolysis inducing factor, thereby attenuating cachexia in patients .5-HT3 antagonists and COX-2 inhibitors have been utilised in cancer cachexia .
Anabolic steroids, due to cytotoxic interactions are prohibited in cancer cachexia and are used only in COPD and HIV-induced cachexia .Conversely, megesterol acetate is commonly used, its mechanism believed to be through indirect and direct stimulation of appetite .Cannabinoids are, although lacking evidence are given by clinicians as adjuvant treatment to cancer patients .Multi-modal treatment is preferable in cancer cachexia, combining all treatment forms to lessen cachexia's impact.
Prevention of Sarcopenia, Current and Future Prospects:
Prevention of sarcopenia has become the mainstay of treatment; loss of lean muscle tissue resulting from progressive aging promotes a challenge to muscle rejuvenation. As a consequence of sarcopenia being a reversible condition, physical exercise and nutrition are the candidates for current prevention rather than pharmacological intervention (8)(12).Pharmacological intervention, whilst remaining relatively research based than clinically applied remains a future concept in sarcopenia treatment.
At present , physical exercise and an adequate diet are the preventative options applied by clinicians , upon identification of those susceptible to sarcopenia , namely elderly individuals .Exercise has been identified in restoring and maintaining muscle function ; physical activity in aging individuals decreases ,parallel to this is decline in fitness and muscle strength(12) .Aerobic training and resistance exercise are usually prescribed to delay muscle loss , aerobic training increasing fitness and oxidative capacity of muscle through swimming , cycling or jogging. Resistance training proves mores beneficial in muscle strength and mass, involving dynamic or static contractions with resistance either with free weight or machines.
Adequate nutrition also bears a role in preventing sarcopenia. In older individuals maintaining a constant BMI rather than reduce their BMI is an important consideration, as malnutrition can precipitate the development of sarcopenia. Obesity in contrast may require BMI alteration for musculoskeletal performance , without loss of lean body tissue .Protein intake with aging decreases , given muscle damage and muscle synthesis alters with progression , increasing essential amino acid consumption therefore theoretically would promote the mTOR nutrient pathway for synthesis .Many trials have had conflicting results of protein supplementation in the elderly , however recent research has illustrated leucine to be a potent stimulator of muscle protein synthesis .Leucine , an essential amino acid is an insulin seratagogue , promoting insulin release and function , combined with activating the mTOR pathway .Adequate protein consumption levels for elderly individuals remains conflicted , according to RDA values , 0.8g/kg/ of protein should be consumed , being spread across three primary meals .Increasing protein consumption to 30g of protein , in both young and older adults leads to a 50% increase in muscle synthesis. This has been emphasised in recent research that showed skeletal muscle synthesis did not respond to low doses of essential amino acids, 7.5g , but higher doses of 10g proved yielding .Conflicting this is a carbohydrate-protein meal , in the elderly , where the synergistic effects of carbohydrates is reversed(14) .
Combining appropriate exercise and diet are regarded as the most adequate measures currently available to defend against sarcopenia. Consistent exercise provides increased sensitisation to consumed protein, from absorption from the intestinal lumen to that of its metabolism in muscle.
Prevention of Sarcopenia, Current and Future Prospects:
Conflict remains around high and low protein supplementation and the benefits it provided in improvements of physical performance, muscle strength and mass .Currently both apt exercise and nutrition regimen remain at the forefront of preventative measures in sarcopenia(14)a.
Future inhibition of sarcopenia encompasses pharmacological measures to both antagonise the inhibitors of muscle synthesis and agonise the promoters, and their respective pathways .Myostatin persists as a topic of research and pharmacological interest(15) , given much of the previous attempted treatments , anabolic hormones , cytokine antagonists and micronutrient supplements have failed with numerous side effects or lacking efficacy(13).
Follistatin, the transgene peptide product, is produced as a 315 amino acid product from skeletal muscle. It was discovered initially as functioning in reproductive physiology, was purified from gonadal fluids and found to regulate FSH. Caveats arising from follistatin use was related to its interference with the hypothalamic-pituitary axis in FSH release and also in the reproductive system .However follistatin is produced as a number of isoforms, FS315 or FS288, this was harnessed in the study by, delivering the FS315 isoform without interrupting the former systems .In the trials conducted under , an adeno-associated virus as used as an adjunct to deliver gene therapy in muscle dystrophy. Experiments on mice found that high-dose follistatin application evoked the greatest muscle weight increase. They hypothesis that follistatin provides a protective effect rather than reversal of the condition, thus allowing the intra-muscular self-correction of the condition. The success of this study equates to translation of follistatin and gene therapy to human trials (16).
Other treatment and prevention measure include combatting the myostatin receptor directly, through monoclonal antibody use against myostatin, thereby preventing its receptor binding .This resulted in increased muscle size, strength and reduced diaphragmatic fibrosis. Another mechanism was to use the myostatin pro-peptide to maintain the myostatin C-terminal inactive, thus inhibiting ActRiia binding .Gene therapy, however is emerging as more efficacious but also less inclined to invoke immune responses, to antibodies or exposure to repeated intramuscular injections.
1. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, and Landi F, et al. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age and ageing [Internet]. 2010 Jul [cited 2012 Oct 11];39(4):412-23. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2886201&tool=pmcentrez&rendertype=abstract
2. Siriett V, Salerno MS, Berry C, Nicholas G, Bower R, Kambadur R, et al. Antagonism of myostatin enhances muscle regeneration during sarcopenia. Molecular therapy : the journal of the American Society of Gene Therapy [Internet]. 2007 Aug 5 [cited 2012 Oct 17];15(8):1463-70. Available from: http://dx.doi.org/10.1038/sj.mt.6300182
3. Sakuma K, Yamaguchi A. Sarcopenia and cachexia: the adaptations of negative regulators of skeletal muscle mass [Internet]. Journal of Cachexia, Sarcopenia and Muscle. [cited 2012 Oct 25]. Available from: http://www.jcsm.info/documents/1202/Sarcopenia and cachexia-the adaptations of negative regulators of skeletal muscle mass.html#CR195
4. Kollias HD, McDermott JC. Transforming growth factor-beta and myostatin signaling in skeletal muscle. Journal of applied physiology (Bethesda, Md. : 1985) [Internet]. 2008 Mar 1 [cited 2012 Oct 16];104(3):579-87. Available from: http://jap.physiology.org/content/104/3/579.full?sid=9b6dc74a-0fcf-452f-b13a-a01bb87ea787
5. 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. Journal of the American Medical Directors Association [Internet]. 2011 May [cited 2012 Oct 17];12(4):249-56. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3377163&tool=pmcentrez&rendertype=abstract
6. Li Y-P, Chen Y, John J, Moylan J, Jin B, Mann DL, et al. TNF-alpha acts via p38 MAPK to stimulate expression of the ubiquitin ligase atrogin1/MAFbx in skeletal muscle. FASEB journal : official publication of the Federation of American Societies for Experimental Biology [Internet]. 2005 Mar [cited 2012 Oct 30];19(3):362-70. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3099533&tool=pmcentrez&rendertype=abstract
7. Li H, Malhotra S, Kumar A. Nuclear factor-kappa B signaling in skeletal muscle atrophy. Journal of molecular medicine (Berlin, Germany) [Internet]. 2008 Oct [cited 2012 Oct 30];86(10):1113-26. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2597184&tool=pmcentrez&rendertype=abstract
8. Lang T, Streeper T, Cawthon P, Baldwin K, Taaffe DR, Harris TB. Sarcopenia: etiology, clinical consequences, intervention, and assessment. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA [Internet]. 2010 Apr [cited 2012 Oct 17];21(4):543-59. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2832869&tool=pmcentrez&rendertype=abstract
9. Stein TP, Wade CE. Metabolic Consequences of Muscle Disuse Atrophy. J. Nutr. [Internet]. 2005 Jul 1 [cited 2012 Nov 7];135(7):1824S-1828. Available from: http://jn.nutrition.org/content/135/7/1824S.full
10. Cachexia: pathophysiology and clinical relevance [Internet]. [cited 2012 Oct 30]. Available from: http://ajcn.nutrition.org/content/83/4/735.full.pdf
11. von Haehling S, Anker SD. Cachexia as a major underestimated and unmet medical need: facts and numbers. Journal of cachexia, sarcopenia and muscle [Internet]. 2010 Sep [cited 2012 Oct 4];1(1):1-5. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3060651&tool=pmcentrez&rendertype=abstract
12. Visvanathan R, Chapman I. Preventing sarcopaenia in older people. Maturitas [Internet]. 2010 Aug [cited 2012 Oct 25];66(4):383-8. Available from: http://dx.doi.org/10.1016/j.maturitas.2010.03.020
13. Malafarina V, Uriz-Otano F, Iniesta R, Gil-Guerrero L. Sarcopenia in the elderly: diagnosis, physiopathology and treatment. Maturitas [Internet]. 2012 Feb [cited 2012 Oct 24];71(2):109-14. Available from: http://dx.doi.org/10.1016/j.maturitas.2011.11.012
14. Paddon-Jones D, Rasmussen BB. Dietary protein recommendations and the prevention of sarcopenia. Current opinion in clinical nutrition and metabolic care [Internet]. 2009 Jan [cited 2012 Nov 6];12(1):86-90. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2760315&tool=pmcentrez&rendertype=abstract
15. Yablonka-Reuveni Z. Myostatin blockade: a new way to enhance skeletal muscle repair in old age? Molecular therapy : the journal of the American Society of Gene Therapy [Internet]. 2007 Aug 16 [cited 2012 Oct 17];15(8):1407-9. Available from: http://dx.doi.org/10.1038/sj.mt.6300248
16. Rodino-Klapac LR, Haidet AM, Kota J, Handy C, Kaspar BK, Mendell JR. Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease. Muscle & nerve [Internet]. 2009 Mar [cited 2012 Nov 6];39(3):283-96. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2717722&tool=pmcentrez&rendertype=abstract
