ReviewMuscle wasting: An overview of recent developments in basic research☆
Introduction
Cachexia sarcopenia and general wasting of the musculature are related to a poor quality of life and increased morbidity / mortality [1]. They are caused by a large number of chronic diseases and the general process of aging thus affecting millions of patients and elderly [2], [3], [4]. The syndrome of cachexia is characterized as complex metabolic abnormalities that lead to the loss of body weight as a consequence of a chronic illness. A consensus statement from 2008 proposed to clinically define cachexia as a non-edematous weight loss exceeding 5% within the previous 3–12 months in combination with symptoms characteristic for cachexia (e.g., fatigue or depression), loss of lean body mass and biochemical abnormalities (e.g., anemia or inflammation) associated with chronic diseases [5]. In adults, a prevalence of 5–15% has been reported in chronic heart failure (CHF) and chronic obstructive pulmonary disease (COPD), while it may be up to 80% in advanced cancer [6]. Interestingly, an estimated 30% of cancer patients die as a result of cachexia rather than the cancer itself [6], although the precise cause of death due to cachexia is still somewhat unclear.
In contrast to the relatively fast atrophy of skeletal muscle associated with cachexia, the syndrome of sarcopenia is characterized by a much slower decline in muscle mass and function that is directly related to the ageing process and may ultimately lead to frailty and loss of independent living [7]. There is a loss of 1–2% of muscle mass per decade of life from the fifth decade onwards, associated with a 1.5% declines in muscle strength, potentially increasing to 3% after the age of 60 [7]. From a histological point of view, sarcopenia is characterized by a decrease in the number and the size of the muscle fibres. The prevalence of sarcopenia for those over 64 years of age has been shown to be 22.6% in women and 26.8% in men, rising to 31.0% and 52.9% respectively in those over 80 years of age [8]. It can thus be estimated that over 3% of the total world population will be affected by sarcopenia by 2015 [8].
However, muscle wasting may also occur independently of chronic diseases and age. Disuse of muscle is a strong inducer of skeletal muscle atrophy and function that is caused by a mechanical unloading of the muscle, e.g. space flight or prolonged bed rest, and involved multiple signaling pathways [9].
The development of preventive and therapeutic strategies against cachexia, sarcopenia and wasting disorders in general is perceived as an urgent need by healthcare professionals [10], [11]. Despite this great medical need, no therapies have been approved for muscle wasting or cachexia in the last decades. Nevertheless, significant efforts to identify new targets are being made by academic groups as well as numerous pharmaceutical companies [12], [13], [14].
Section snippets
Current developments in basic cachexia research
The mass of a muscle is determined by dynamic regulation of its protein balance in the muscle fibers in response to various extracellular stimuli that can be anabolic or catabolic in nature. These signals may also affect the proliferation and maturation of muscle stem cells. Potent anabolic signals in skeletal muscle are insulin, insulin like growth factor-1 (IGF-1) [15], testosterone [16] and agonists of the β-2 adrenoreceptor [17]. Levels of IGF-1 are regulated by the ghrelin / growth hormone
News in catabolic signaling
In healthy individuals muscle growth is limited by several members of the TGF-β family, namely myostatin, activin A and TGF-β binding to the activin IIB receptor or the TGF-β receptor, respectively. Under disease conditions, these proteins prominently contribute to the induction of protein loss in skeletal muscle [30], [31]. Activation of either receptor induces SMAD2/SMAD3 signaling resulting in inhibition of anabolic Akt-signaling and stimulation of proteolysis [19], [30]. Cytokines like
News in anabolic signaling
It has been well established that GH, IGF-1, and insulin are potent anabolic factors in skeletal muscle, promoting muscle mass gain. GH primarily regulates liver IGF-1 expression with downstream anabolic effects in skeletal muscle. Insulin and GH are also involved in fat metabolism: GH induces lipolysis and insulin promotes synthesis of fatty acids in the liver and inhibits their degradation in adipose tissue [15]. However, the GH/IGF-1 axis is controlled by various factors, including ghrelin
Biomarkers
A major difficulty in developing anti-wasting therapy strategies and novel drugs is the precise assessment of skeletal muscle mass and any changes during the studies. Currently, wasting assessment is limited to imaging-related quantification of muscle mass by either magnetic resonance imaging (MRI), computed tomography (CT), or dual energy x-ray absorptiometry scan (DEXA) and functional tests to quantify muscle function. Unfortunately, they are all cost-intensive and only available at big
Conflict of interest
The authors report no relationships that could be construed as a conflict of interest.
Acknowledgements
This manuscript complies with the ethical standards in publishing scientific articles in the International Journal of Cardiology family of journals.
References (80)
- et al.
Cachexia: a new definition
Clin Nutr
(2008) - et al.
Mitochondrial dysfunction and sarcopenia of aging: from signaling pathways to clinical trials
Int J Biochem Cell Biol
(2013) - et al.
Tandospirone reduces wasting and improves cardiac function in experimental cancer cachexia
Int J Cardiol
(2013) - et al.
Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival
Cell
(2010) - et al.
Crosstalk between glucocorticoid receptor and nutritional sensor mTOR in skeletal muscle
Cell Metab
(2011) - et al.
SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2
J Biol Chem
(2002) - et al.
The CUL7 E3 ubiquitin ligase targets insulin receptor substrate 1 for ubiquitin-dependent degradation
Mol Cell
(2008) - et al.
The SCF-Fbxo40 complex induces IRS1 ubiquitination in skeletal muscle, limiting IGF1 signaling
Dev Cell
(2011) - et al.
Myostatin/activin pathway antagonism: molecular basis and therapeutic potential
Int J Biochem Cell Biol
(2013) - et al.
The ubiquitin ligase Mul1 induces mitophagy in skeletal muscle in response to muscle-wasting stimuli
Cell Metab
(2012)
Effect of application route of the ghrelin analog BIM-28131 (RM-131) on body weight and body composition in a rat heart failure model
Int J Cardiol
Why cachexia kills: examining the causality of poor outcomes in wasting conditions
J Cachexia Sarcopenia Muscle
From muscle wasting to sarcopenia and myopenia: update 2012
J Cachexia Sarcopenia Muscle
Cachexia vs obesity: where is the real unmet clinical need?
J Cachexia Sarcopenia Muscle
Cachexia as a major public health problem: frequent, costly, and deadly
J Cachexia Sarcopenia Muscle
Cachexia as a major underestimated and unmet medical need: facts and numbers
J Cachexia Sarcopenia Muscle
An overview of sarcopenia: facts and numbers on prevalence and clinical impact
J Cachexia Sarcopenia Muscle
Prevalence of sarcopenia and predictors of skeletal muscle mass in healthy, older men and women
J Gerontol A Biol Sci Med Sci
Skeletal muscle wasting with disuse atrophy is multi-dimensional: the response and interaction of myonuclei, satellite cells and signaling pathways
Front Physiol
Role and potential mechanisms of anabolic resistance in sarcopenia
J Cachexia Sarcopenia Muscle
Abstracts of the 7th cachexia conference, kobe/osaka, Japan, december 9–11, 2013
J Cachexia Sarcopenia Muscle
Abstracts of the 7th cachexia conference, kobe/osaka, Japan, december 9–11, 2013 (part 2)
J Cachexia Sarcopenia Muscle
Cancer cachexia: impact, mechanisms and emerging treatments
J Cachexia Sarcopenia Muscle
Growth hormone, insulin-like growth factor 1, and insulin signaling-a pharmacological target in body wasting and cachexia
J Cachexia Sarcopenia Muscle
Low testosterone levels and increased inflammatory markers in patients with cancer and relationship with cachexia
J Clin Endocrinol Metab
Formoterol treatment downregulates the myostatin system in skeletal muscle of cachectic tumour-bearing rats
Oncol Lett
Ghrelin for cachexia
J Cachexia Sarcopenia Muscle
Regulation of skeletal muscle growth by the IGF1-Akt/PKB pathway: insights from genetic models
Skelet Muscle
Hypogonadism in male cancer patients
J Cachexia Sarcopenia Muscle
The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial
J Cachexia Sarcopenia Muscle
Prevention of liver cancer cachexia-induced cardiac wasting and heart failure
Eur Heart J
Inflammation, organomegaly, and muscle wasting despite hyperphagia in a mouse model of burn cachexia
J Cachexia Sarcopenia Muscle
The effect of exercise on IL-6-induced cachexia in the Apc ( Min/+) mouse
J Cachexia Sarcopenia Muscle
Angiotensin II infusion induces marked diaphragmatic skeletal muscle atrophy
PLoS One
Hypomanic episode as a first presentation of a large B-cell lymphoma
Jpn J Clin Oncol
The role of myostatin in muscle wasting: an overview
J Cachexia Sarcopenia Muscle
Signaling pathways controlling skeletal muscle mass
Crit Rev Biochem Mol Biol
Myostatin blockage using actRIIB antagonism in mice bearing the Lewis lung carcinoma results in the improvement of muscle wasting and physical performance
J Cachexia Sarcopenia Muscle
TNF-alpha- and tumor-induced skeletal muscle atrophy involves sphingolipid metabolism
Skelet Muscle
Metabolic derangements in the gastrocnemius and the effect of Compound A therapy in a murine model of cancer cachexia
J Cachexia Sarcopenia Muscle
Cited by (0)
- ☆
Disclosure: This paper is also published in parallel in the Journal of Cachexia, Sarcopenia and Muscle.