Review
Muscle wasting: An overview of recent developments in basic research

https://doi.org/10.1016/j.ijcard.2014.08.086Get rights and content

Highlights

  • Review of potential anti-catabolic targets (E-3 ubiquitin ligases, MST1 kinase)

  • Novel anabolic G-protein Gαi2

  • D(3)-creatine has the potential biomarker for changes in skeletal muscle mass

Abstract

The syndrome of cachexia, i.e. involuntary weight loss in patients with underlying diseases, sarcopenia, i.e. loss of muscle mass due to ageing, and general muscle atrophy from disuse and/or prolonged bed rest have received more attention over the last decades. All lead to a higher morbidity and mortality in patients and therefore, they represent a major socio-economic burden for the society today.

This mini-review looks at recent developments in basic research that are relevant to the loss of skeletal muscle. It aims to cover the most significant publication of last three years on the causes and effects of muscle wasting, new targets for therapy development and potential biomarkers for assessing skeletal muscle mass. The targets include 1) E-3 ligases: TRIM32, SOCS1 and SOCS3 by involving the elongin BC ubiquitin-ligase, Cbl-b, culling 7, Fbxo40, MG53 (TRIM72) and the mitochondrial Mul1, 2) the kinase MST1 and 3) the G-protein Gαi2. D(3)-creatine has the potential to be used as a novel biomarker that allows to monitor actual change in skeletal muscle mass over time.

In conclusion, significant development efforts are being made by academic groups as well as numerous pharmaceutical companies to identify new targets and biomarkers muscle, as muscle wasting represents a great medical need, but no therapies have been approved in the last decades.

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.

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    Disclosure: This paper is also published in parallel in the Journal of Cachexia, Sarcopenia and Muscle.

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