Molecular determinants of skeletal muscle mass: getting the “AKT” together

Abstract

Skeletal muscle is the most abundant tissue in the human body and its normal physiology plays a fundamental role in health and disease. During many disease states, a dramatic loss of skeletal muscle mass (atrophy) is observed. In contrast, physical exercise is capable of producing significant increases in muscle mass (hypertrophy). Maintenance of skeletal muscle mass is often viewed as the net result of the balance between two separate processes, namely protein synthesis and protein degradation. However, these two biochemical processes are not occurring independent of each other but they rather appear to be finely coordinated by a web of intricate signaling networks. Such signaling networks are in charge of executing environmental and cellular cues that will ultimate determine whether muscle proteins are synthesized or degraded. In this review, recent findings are discussed demonstrating that the AKT1/FOXOs/Atrogin-1(MAFbx)/MuRF1 signaling network plays an important role in the progression of skeletal muscle atrophy. These novel findings highlight an important mechanism that coordinates the activation of the protein synthesis machinery with the activation of a genetic program responsible for the degradation of muscle proteins during skeletal muscle atrophy.

Introduction

Skeletal muscle is the most abundant tissue in the human body accounting for ∼50% of the total body mass. It is not only the major site of metabolic activity but it is also the largest protein reservoir, serving as a source of amino acids to be utilized for energy production during periods of food deprivation, and playing a central role in nitrogen flow during some disease states. Over the years, a large body of evidence has suggested that in many disease states or unfavorable environmental conditions, skeletal muscle mass could be markedly reduced, a condition that may have devastating health consequences. In contrast, some forms of physical activity such as resistance exercise, can produce large increases in skeletal muscle mass. Clearly these two contrasting situations represent both ends of a continuum of mechanisms involved in balancing the forces that regulate skeletal muscle mass. Understanding such mechanisms could lead to a better management of the loss of skeletal muscle.

Two recent studies have further expanded our knowledge about the mechanisms involved in the development of skeletal muscle atrophy. In these reports, Sandri et al. (2004) and Stitt et al. (2004) together with their respective co-workers have provided direct evidence for a role of AKT1 signaling as a modulator of the expression of two important genes involved in the progression of muscle atrophy, the E3 ubiquitin ligases atrogin-1 or Muscle Atrophy F box (MAFbx) and the Muscle Ring Finger-1 (MuRF-1), and their regulation by a family of transcription factors termed Forkhead box O (FOXO). Therefore the specific goal of the present review is to discuss the role of AKT1 as a regulator of the expression of these atrophy-related genes via the FOXO family of transcription factors (FOXOs) and the integration of such mechanism in a signaling network previously characterized involving AKT1 signaling in the activation of the protein synthetic machinery. Exciting new evidence demonstrates that the expression of atrogin-1 (MAFbx) and MURF-1 is controlled by a signaling network that comprises FOXOs and their regulation by AKT1. These new findings are important not only from the atrophy standpoint, but also from the integration of cellular regulatory networks perspective as they created a scenario in which a key molecule that is positively involved in cellular growth (via protein synthesis) when in its active state, also negatively regulates the opposite process (protein degradation). Such interaction suggests that the dynamic regulation of skeletal muscle mass is not simply the balance between protein synthesis and degradation but is a rather finely coordinate process.