Cachexia and sarcopenia: mechanisms and potential targets for intervention

doi:10.1016/j.coph.2015.04.003

Current Opinion in Pharmacology

Volume 22, June 2015, Pages 100-106

https://doi.org/10.1016/j.coph.2015.04.003 Get rights and content

Highlights

•
Cachexia and sarcopenia share common trends: altered protein synthesis and degradation.
•
Cachexia and sarcopenia are both driven by inflammation.
•
Sarcopenia is ameliorated by resistance training, ingestion of AA, and testosterone.
•
Cachexia is ameliorated by progestagens, corticosteroids, ghrelin agonists, myostatin antagonists and SARMs.

Cachexia is a multi-organ syndrome associated with cancer and other chronic diseases, characterized by body weight loss, muscle and adipose tissue wasting and inflammation, being often associated with anorexia. Skeletal muscle tissue represents more than 40% of body weight and seems to be one of the main tissues involved in the wasting that occurs during cachexia. Sarcopenia is a degenerative loss of skeletal muscle mass, quality, and strength associated with healthy ageing. The molecular mechanisms behind cachexia and sarcopenia share some common trends. Muscle wasting is the result of a combination of an imbalance between synthetic and degradative protein pathways together with increased myocyte apoptosis and decreased regenerative capacity. Oxidative pathways are also altered in skeletal muscle during muscle wasting and this seems to be a consequence of mitochondrial abnormalities that include altered morphology and function, decreased ATP synthesis and uncoupling. The aim of the present review is to analyse common molecular pathways between cachexia and sarcopenia in order to put forward 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)

W.J. Evans et al.
Cachexia: a new definition
Clin Nutr
(2008)
J.M. Argilés et al.
Consensus on cachexia definitions
J Am Med Dir Assoc
(2010)
K. Fearon et al.
Definition and classification of cancer cachexia: an international consensus
Lancet Oncol
(2011)
M. Muscaritoli 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)
J.E. Morley et al.
Sarcopenia with limited mobility: an international consensus
J Am Med Dir Assoc
(2011)
C.M.M. Prado 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)
G. Biolo 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)
A.A. Tzika et al.
Skeletal muscle mitochondrial uncoupling in a murine cancer cachexia model
Int J Oncol
(2013)
F. Okada
Inflammation and free radicals in tumor development and progression
Redox Rep
(2002)
S. Venkatesh et al.
Multitasking in the mitochondrion by the ATP-dependent Lon protease
Biochim Biophys Acta
(2012)

A.R. Konopka et al.

Mitochondrial and skeletal muscle health with advancing age

Mol Cell Endocrinol

(2013)

M.R. Beltran Valls et al.

Protein carbonylation and heat shock proteins in human skeletal muscle: relationships to age and sarcopenia

J Gerontol A: Biol Sci Med Sci

(2015)

V.B. Vays et al.

Antioxidant SkQ1 delays sarcopenia-associated damage of mitochondrial ultrastructure [Internet]

Aging (Albany, NY)

(2014)

J.D. Walston et al.

Inflammation and stress-related candidate genes, plasma interleukin-6 levels, and longevity in older adults

Exp Gerontol

(2009)

M.D. Grounds

Reasons for the degeneration of ageing skeletal muscle: a central role for IGF-1 signalling

Biogerontology

(2002)

K. Sakuma et al.

Novel intriguing strategies attenuating to sarcopenia

J Aging Res

(2012)

K. Tanaka et al.

Active vitamin D possesses beneficial effects on the interaction between muscle and bone

Biochem Biophys Res Commun

(2014)

A.J. Cruz-Jentoft et al.

Sarcopenia: European consensus on definition and diagnosis: report of the European Working Grop on Sarcopenia in Older People

Age Ageing

(2010)

R. Sambasivan et al.

Adult skeletal muscle stem cells

Results Probl Cell Differ

(2015)

J.M. Argilés et al.

Cancer cachexia: understanding the molecular basis

Nat Rev Cancer

(2014)

D.A. Rivas et al.

Diminished skeletal muscle microRNA expression with aging is associated with attenuated muscle plasticity and inhibition of IGF-1 signaling

FASEB J

(2014)

N. Tardif et al.

Muscle ectopic fat deposition contributes to anabolic resistance in obese sarcopenic old rats through eIF2α activation

Aging Cell

(2014)

A.M. Shum et al.

Disruption of MEF2C signaling and loss of sarcomeric and mitochondrial integrity in cancer-induced skeletal muscle wasting

Aging (Albany NY)

(2012)

C.M. Julienne et al.

Cancer cachexia is associated with a decrease in skeletal muscle mitochondrial oxidative capacities without alteration of ATP production efficiency

J Cachexia Sarcopenia Muscle

(2012)

Cited by (213)

Association between Sarcopenia and Survival in Patients Undergoing Gamma Knife Surgery for Brain Metastasis from Breast Cancer: A Retrospective Single-centre Cohort Study
2024, Clinical Oncology
Many recent studies related to cancer surgery have reported that sarcopenia influences mortality in surgical patients. However, few comprehensive studies have examined the associations between sarcopenia and short- and long-term surgical outcomes of metastatic cancer, especially breast cancer with brain metastasis. In the present study, we investigated the association between sarcopenia and mortality in patients who underwent gamma knife radiosurgery (GKRS) for brain metastasis with breast cancer.
This retrospective study analysed 157 patients who underwent GKRS for brain metastasis with breast cancer between January 2014 and December 2018. A Cox regression analysis was carried out to evaluate the association between sarcopenia and mortality at 90 days, 180 days, 1 year, 3 years and the overall period.
In the Cox regression analysis, sarcopenia was significantly associated with high 90-day mortality (adjusted hazard ratio 3.46, 95% confidence interval 1.24–9.67, P = 0.018), 180-day mortality (adjusted hazard ratio 2.67, 95% confidence interval 1.37–5.22, P = 0.004), 1-year mortality (adjusted hazard ratio 2.39, 95% confidence interval 1.42–4.02, P = 0.001), 3-year mortality (adjusted hazard ratio 2.39, 95% confidence interval 1.53–3.74, P < 0.001) and overall mortality (adjusted hazard ratio 2.11, 95% confidence interval 1.37–3.26, P < 0.001).
Sarcopenia could be a risk factor for short- and long-term mortality in patients undergoing GKRS for brain metastasis from breast cancer.
Identification of key genes and signaling pathways based on transcriptomic studies of aerobic and resistance training interventions in sarcopenia in SAMP8 mice
2024, Sports Medicine and Health Science
We examined the effects of resistance and aerobic exercise on the gene expression and biometabolic processes of aging skeletal muscle in senescence-accelerated mouse/prone 8 mice, a model of sarcopenia, and compared them with senescence-accelerated mouse/resistant 1 mice acting as controls. We found that exercise improved muscle strength, endurance, fiber size, also modulated genes and pathways related to synaptic transmission, potassium transport, JAK-STAT signaling, and PI3K-Akt signaling. Our results suggested that BDNF, JAK2, RhoC, Myh6, Stat5a, Tnnc1, and other genes may mediate the beneficial effects of exercise on sarcopenia through these pathways.
Body composition analysis using convolutional neural network in predicting postoperative pancreatic fistula and survival after pancreatoduodenectomy for pancreatic cancer
2023, European Journal of Radiology
To evaluate whether body composition measurements acquired using convolutional neural networks (CNNs) from preoperative CT images could predict postoperative pancreatic fistula (POPF) and overall survival (OS) after pancreaticoduodenectomy in patients with pancreatic ductal adenocarcinoma (PDAC).
257 patients (160 men; median age [interquartile range], 67 [60–74]) who underwent pancreaticoduodenectomy for PDAC between January 2013 and December 2017 were included in this retrospective study. Body composition measurements were based on a CNN trained to segment CT images into skeletal muscle area, visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT). Skeletal muscle area, VAT, and SAT were normalized to height square and labeled as skeletal muscle, VAT, and SAT indices, respectively. The independent risk factors for clinically relevant POPF (grade B or C) were determined using a multivariate logistic regression model, and prognostic factors for OS were assessed using Cox proportional hazards regression analyses.
After pancreatioduodenectomy, 27 patients developed POPF grade B or C (10.5 %, 27/257). The VAT index (odds ratio [OR] = 7.43, p < 0.001) was the only independent prognostic factor for POPF grade B or C. During the median follow-up period of 23 months, 205 (79.8 % [205/257]) patients died. For prediction of OS, skeletal muscle index (hazard ratio [HR] = 0.58, p = 0.018) was a significant factor, along with vascular invasion (HR = 1.85, p < 0.001) and neoadjuvant therapy (HR = 0.58, p = 0.011).
A high VAT index and a low skeletal muscle index can be utilized in predicting the occurrence of POPF grade B or C and poor OS, respectively.
Association of Sarcopenia With Mortality in Patients With Chronic Limb-Threatening Ischemia Undergoing Endovascular Revascularization
2023, Journal of Surgical Research
Chronic limb-threatening ischemia (CLTI) is the most severe form of peripheral artery disease and leads high mortality. Sarcopenia, characterized by the loss of muscle mass or poor muscle quality, is associated with adverse clinical outcomes. This study aimed to investigate the association between sarcopenia and the long-term outcomes in patients with CLTI after endovascular revascularization.
We retrospectively reviewed the medical records of all patients with CLTI who underwent endovascular revascularization between January 2015, and December 2021. The skeletal muscle area was calculated at the third lumbar vertebra from computed tomography images using the manual trace method and normalized to patient height. Sarcopenia was defined as a third lumbar skeletal muscle index of <40.8 cm²/m² in males and <34.9 cm²/m² in females. The Kaplan–Meier and Cox proportional hazards regression analyses were used for survival analysis and to evaluate the association between sarcopenia and mortality.
A total of 137 patients (90 men; mean age 71.7 ± 9.6 y) were enrolled for the study, of whom 56 (40.8%) had sarcopenia. The 3-year overall survival rate in patients with CLTI who underwent endovascular revascularization was 71.2%. The sarcopenic group had a significantly worse 3-year overall survival rate than the nonsarcopenic group (55.3% versus 78.6%, P = 0.001). Multivariate Cox proportional hazard regression analyses revealed that sarcopenia (hazard ratio, 2.262; 95% confidence interval, 1.132-4.518; P = 0.021) and dialysis (hazard ratio, 3.021; 95% confidence interval, 1.337-6.823; P = 0.008) were independently associated with increased risk of all-cause mortality, whereas technical success had significantly opposing correlation with mortality. (hazard ratio, 0.400, 95% confidence interval, 0.194-0.826, P = 0.013).
Sarcopenia can be highly prevalent in patients with CLTI who undergo endovascular revascularization, and is independently associated with long-term mortality. These results may help risk stratification to assist in personalized assessment and clinical decision-making.
Survival and immunotoxicities in association with sex-specific body composition patterns of cancer patients undergoing immune-checkpoint inhibitor therapy – A systematic review and meta-analysis
2023, European Journal of Cancer
Imbalanced body composition is mechanistically connected to dysregulated immune activities. Whether overweight/obesity or sarcopenia has an impact on treatment results in cancer patients undergoing immune checkpoint inhibitor (ICI) therapy is currently under debate. We aimed to answer if survival rates and occurrence of immune-related adverse events (irAEs) were different in obese or sarcopenic patients.
A systematic search was conducted in PubMed, Embase and CENTRAL for all records published until July 2022 using specific search terms for body composition in combination with terms for ICI regimens. Two authors screened independently. All studies that reported on body mass index or sarcopenia measures were selected for further analysis.
48 studies reporting on overweight/obesity comprising of 19,767 patients, and 32 studies reporting on sarcopenia comprising of 3193 patients fulfilled the inclusion criteria. In the entire cohort, overweight/obesity was significantly associated with better progression-free survival (PFS; p = 0.009) and overall survival (OS; p <0.00001). Subgroup analyses stratified by sex revealed that overweight/obese males had the strongest survival benefit (PFS: p = 0.05; OS: p = 0.0005), and overweight/obese female patients did not show any. However, overweight/obese patients of both sexes had a higher risk to develop irAEs grade ≥3 (p = 0.0009). Sarcopenic patients showed significantly shorter PFS (p <0.0001) and OS (p <0.0001). The frequency of irAEs did not differ between sarcopenic and non-sarcopenic patients.
This meta-analysis suggests that body composition is associated in a sex-specific manner with survival and irAEs in cancer patients undergoing ICI treatment.
Oropharyngeal cancer associated with sarcopenic obesity and sarcopenic weight loss
2022, Oral Oncology

View all citing articles on Scopus

View full text

Cachexia and sarcopenia: mechanisms and potential targets for intervention

Highlights

Section snippets

Cachexia and sarcopenia: definitions and common trends

Muscle wasting

Oxidative damage and mitochondrial dysfunction

The role of cytokines

Therapeutic approaches to ameliorate muscle wasting

Conclusions and future directions

Conflict of interest statement

References and recommended reading

Acknowledgements

Clin Nutr

J Am Med Dir Assoc

Lancet Oncol

Clin Nutr

J Am Med Dir Assoc

Lancet Oncol

Clin Nutr

Int J Oncol

Redox Rep

Biochim Biophys Acta

Mol Cell Endocrinol

J Gerontol A: Biol Sci Med Sci

Aging (Albany, NY)

Exp Gerontol

Biogerontology

J Aging Res

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