Therapeutic approaches for muscle wasting disorders

Abstract

Muscle wasting and weakness are common in many disease states and conditions including aging, cancer cachexia, sepsis, denervation, disuse, inactivity, burns, HIV-acquired immunodeficiency syndrome (AIDS), chronic kidney or heart failure, unloading/microgravity, and muscular dystrophies. Although the maintenance of muscle mass is generally regarded as a simple balance between protein synthesis and protein degradation, these mechanisms are not strictly independent, but in fact they are coordinated by a number of different and sometimes complementary signaling pathways. Clearer details are now emerging about these different molecular pathways and the extent to which these pathways contribute to the etiology of various muscle wasting disorders.

Therapeutic strategies for attenuating muscle wasting and improving muscle function vary in efficacy. Exercise and nutritional interventions have merit for slowing the rate of muscle atrophy in some muscle wasting conditions, but in most cases they cannot halt or reverse the wasting process. Hormonal and/or other drug strategies that can target key steps in the molecular pathways that regulate protein synthesis and protein degradation are needed. This review describes the signaling pathways that maintain muscle mass and provides an overview of some of the major conditions where muscle wasting and weakness are indicated. The review provides details on some therapeutic strategies that could potentially attenuate muscle atrophy, promote muscle growth, and ultimately improve muscle function. The emphasis is on therapies that can increase muscle mass and improve functional outcomes that will ultimately lead to improvement in the quality of life for affected patients.

Introduction

Many different conditions are associated with skeletal wasting and weakness. Muscle wasting can occur as a consequence of diseases such as muscular dystrophies or cancer (cachexia). Similarly, aging is associated with a progressive loss of muscle leading to increasing frailty, weakness, and loss of functional independence. The mechanisms underlying the loss of skeletal muscle differ between the various conditions, thus therapies used to combat wasting and restore muscle function will also differ. For example, the loss of muscle mass may have a neurogenic origin (e.g., denervation), or it could result from cytokine elevation activating protein degradative pathways (e.g., cancer cachexia, HIV-acquired immunodeficiency syndrome [AIDS]). This knowledge is important since a severe loss of functional muscle mass contributes to patient mortality.

Muscles maintain their mass and function because of a balance between protein synthesis and protein degradation associated with equal rates of anabolic and catabolic processes, respectively. Muscles grow (hypertrophy) when protein synthesis exceeds protein degradation. Conversely, muscles shrink (atrophy) when protein degradation dominates. Understanding the pathways that regulate skeletal muscle mass is crucial for the development of successful nutritional or drug interventions that can attenuate wasting and weakness and improve muscle structure and function.

There have been several recent reviews devoted to intracellular signaling during skeletal muscle atrophy and hypertrophy (Jackman and Kandarian, 2004, Rennie et al., 2004, Attaix et al., 2005, Bartoli and Richard, 2005, Cao et al., 2005, Costelli et al., 2005, Glass, 2005, Nader, 2005, Nair, 2005, Bassel-Duby and Olson, 2006, Kandarian and Jackman, 2006) and the purpose of this review is not to simply repeat this information. Rather, this review is designed to provide an overview of some of the major conditions where muscle wasting and weakness are indicated and also to provide information on some therapeutic strategies that could potentially attenuate muscle atrophy, promote muscle growth, and ultimately improve muscle function. This review differs from other reviews in that our discussion is biased toward therapies that do not just modulate muscle structure but instead emphasizes those approaches that could improve functional outcomes that would meaningfully improve patient quality of life.

The major pathways leading to muscle breakdown are the ubiquitin-proteasome pathway (Attaix et al., 2005, Cao et al., 2005, Tisdale, 2005), calpain-calpastatin pathway (Bartoli and Richard, 2005, Costelli et al., 2005, Hasselgren et al., 2005), lysosomal pathway (Farges et al., 2002, Busquets et al., 2006), and apoptosis or programmed cell death (Lee et al., 2004, Leeuwenburgh et al., 2005, Siu and Alway, 2006). The muscle wasting which occurs in the majority of disorders, can be explained by activation of one or more of these pathways. However, not all pathways are activated in every condition. We will first identify a number of different muscle wasting conditions and describe the mechanisms responsible for the loss of muscle mass (and associated weakness) in each case. We will then describe a number of different therapeutic approaches for attenuating muscle wasting and weakness.