Cachexia and sarcopenia: mechanisms and potential targets for intervention
Section snippets
Cachexia and sarcopenia: definitions and common trends
Cachexia is a multi-organ syndrome associated with diseases such as cancer, chronic infection, chronic obstructive pulmonary disease, chronic heart failure and others, characterized by body weight loss (at least 5%), muscle and adipose tissue wasting and inflammation, and often anorexia. Associated with cachexia we find alterations in carbohydrate, lipid and protein metabolism. According to an international consensus [1]: ‘cachexia, is a complex metabolic syndrome associated with underlying
Muscle wasting
The cachectic state is clearly hypercatabolic due to the activation of both fat and protein degradation by the systemic inflammatory response. The main event that takes place in the skeletal muscle of the cachectic patient is a huge increase in the rate of skeletal muscle proteolysis (Table 1). Different proteolytic mechanisms are involved, the ubiquitin-dependent pathway being the most important. Increased muscle myocyte apoptosis, and a lack of differentiation of satellite cells [9] also
Oxidative damage and mitochondrial dysfunction
Distorted mitochondria are present in muscle during cancer cachexia [13] and this is associated with loss of skeletal muscle structural integrity. Different research groups have shown that, in spite of the fact that the UCP2 gene is overexpressed in skeletal muscle from cachectic rats [14, 15] and that muscle oxidative capacity — complex IV activity — is decreased, no alteration in either ATP synthesis or uncoupling are observed. These results are in contrast to the observation from our own
The role of cytokines
As widely demonstrated, cytokines — either released by the tumour or by immune cells, activate many of the altered metabolic pathways present in skeletal muscle wasting, such as increased proteolysis, myocyte apoptosis or decreased amino acid transport and regeneration [10••]. At the mitochondrial level, some cytokines activate the transcriptional PGC-1α, through phosphorylation by p38 kinase, resulting in stabilization and activation of PGC-1α⋅ This causes increased respiration and expression of
Therapeutic approaches to ameliorate muscle wasting
Currently available data show that human sarcopenia is attenuated by resistance training, the ingestion of amino acids, and treatment with testosterone [42••]. The results of nutrition interventions are equivocal due to the low number of studies and heterogeneous study design. Essential amino acid (EAA) supplements, including ∼2.5 g of leucine, and β-hydroxy β-methylbutyric acid (HMB) supplements, show some effects in improving muscle mass and function parameters. Protein supplements have not
Conclusions and future directions
At the molecular level, cachexia and sarcopenia share common trends, which can be summarized in two different considerations (Table 1). First, inflammation is, in both cases, the driving force of the molecular alterations that affect, particularly, skeletal muscle. Indeed, loss of muscle mass affects strength and function and is the result of different events including increased protein degradation, decreased protein synthesis, increased myocyte apoptosis and decreased muscle regeneration
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by a grant from the Ministerio de Ciencia y Tecnología (SAF 26091-2011).
References (49)
- et al.
Cachexia: a new definition
Clin Nutr
(2008) - et al.
Consensus on cachexia definitions
J Am Med Dir Assoc
(2010) - et al.
Definition and classification of cancer cachexia: an international consensus
Lancet Oncol
(2011) - et al.
Consensus definition of sarcopenia, cachexia and pre-cachexia: joint document elaborated by Special Interest Groups (SIG) “cachexia-anorexia in chronic wasting diseases” and “nutrition in geriatrics”
Clin Nutr
(2010) - et al.
Sarcopenia with limited mobility: an international consensus
J Am Med Dir Assoc
(2011) - et al.
Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study
Lancet Oncol
(2008) - et al.
Muscle contractile and metabolic dysfunction is a common feature of sarcopenia of aging and chronic diseases: from sarcopenic obesity to cachexia
Clin Nutr
(2014) - et al.
Skeletal muscle mitochondrial uncoupling in a murine cancer cachexia model
Int J Oncol
(2013) Inflammation and free radicals in tumor development and progression
Redox Rep
(2002)- et al.
Multitasking in the mitochondrion by the ATP-dependent Lon protease
Biochim Biophys Acta
(2012)
Mitochondrial and skeletal muscle health with advancing age
Mol Cell Endocrinol
Protein carbonylation and heat shock proteins in human skeletal muscle: relationships to age and sarcopenia
J Gerontol A: Biol Sci Med Sci
Antioxidant SkQ1 delays sarcopenia-associated damage of mitochondrial ultrastructure [Internet]
Aging (Albany, NY)
Inflammation and stress-related candidate genes, plasma interleukin-6 levels, and longevity in older adults
Exp Gerontol
Reasons for the degeneration of ageing skeletal muscle: a central role for IGF-1 signalling
Biogerontology
Novel intriguing strategies attenuating to sarcopenia
J Aging Res
Active vitamin D possesses beneficial effects on the interaction between muscle and bone
Biochem Biophys Res Commun
Sarcopenia: European consensus on definition and diagnosis: report of the European Working Grop on Sarcopenia in Older People
Age Ageing
Adult skeletal muscle stem cells
Results Probl Cell Differ
Cancer cachexia: understanding the molecular basis
Nat Rev Cancer
Diminished skeletal muscle microRNA expression with aging is associated with attenuated muscle plasticity and inhibition of IGF-1 signaling
FASEB J
Muscle ectopic fat deposition contributes to anabolic resistance in obese sarcopenic old rats through eIF2α activation
Aging Cell
Disruption of MEF2C signaling and loss of sarcomeric and mitochondrial integrity in cancer-induced skeletal muscle wasting
Aging (Albany NY)
Cancer cachexia is associated with a decrease in skeletal muscle mitochondrial oxidative capacities without alteration of ATP production efficiency
J Cachexia Sarcopenia Muscle
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