p21-Activated Kinase 1 Is Permissive for the Skeletal Muscle Hypertrophy Induced by Myostatin Inhibition

The transforming growth factor-beta (TGF-beta) superfamily encompasses a large group of growth and differentiation factors playing important roles in regulating embryonic development and in maintaining tissue homeostasis in adult animals. Using degenerate polymerase chain reaction, we have identified a new murine TGF-beta family member, growth/differentiation factor-8 (GDF-8), which is expressed specifically in developing and adult skeletal muscle. During early stages of embryogenesis, GDF-8 expression is restricted to the myotome compartment of developing somites. At later stages and in adult animals, GDF-8 is expressed in many different muscles throughout the body. To determine the biological function of GDF-8, we disrupted the GDF-8 gene by gene targeting in mice. GDF-8 null animals are significantly larger than wild-type animals and show a large and widespread increase in skeletal muscle mass. Individual muscles of mutant animals weigh 2-3 times more than those of wild-type animals, and the increase in mass appears to result from a combination of muscle cell hyperplasia and hypertrophy. These results suggest that GDF-8 functions specifically as a negative regulator of skeletal muscle growth.

The p21-activated kinases (PAKs) 1-3 are serine/threonine protein kinases whose activity is stimulated by the binding of active Rac and Cdc42 GTPases. Our understanding of the regulation and biology of these important signaling proteins has increased tremendously since their discovery in the mid-1990s. PAKs 1-3 are activated by a variety of GTPase-dependent and -independent mechanisms. This complexity reflects the contributions of PAK function in many cellular signaling pathways and the need to carefully control PAK action in a highly localized manner. PAKs serve as important regulators of cytoskeletal dynamics and cell motility, transcription through MAP kinase cascades, death and survival signaling, and cell-cycle progression. Consequently, PAKs have also been implicated in a number of pathological conditions and in cell transformation. We propose here a key role for PAK action in coordinating the dynamics of the actin and microtubule cytoskeletons during directional motility of cells, as well as in other functions requiring cytoskeletal polarization.

Many pathological states characterized by muscle atrophy (e.g., sepsis, cachexia, starvation, metabolic acidosis and severe insulinopenia) are associated with an increase in circulating glucocorticoids (GC) levels, suggesting that GC could trigger the muscle atrophy observed in these conditions. GC-induced muscle atrophy is characterized by fast-twitch, glycolytic muscles atrophy illustrated by decreased fiber cross-sectional area and reduced myofibrillar protein content. GC-induced muscle atrophy results from increased protein breakdown and decreased protein synthesis. Increased muscle proteolysis, in particular through the activation of the ubiquitin proteasome and the lysosomal systems, is considered to play a major role in the catabolic action of GC. The stimulation by GC of these two proteolytic systems is mediated through the increased expression of several Atrogenes ("genes involved in atrophy"), such as FOXO, Atrogin-1, and MuRF-1. The inhibitory effect of GC on muscle protein synthesis is thought to result mainly from the inhibition of the mTOR/S6 kinase 1 pathway. These changes in muscle protein turnover could be explained by changes in the muscle production of two growth factors, namely Insulin-like Growth Factor (IGF)-I, a muscle anabolic growth factor and Myostatin, a muscle catabolic growth factor. This review will discuss the recent progress made in the understanding of the mechanisms involved in GC-induced muscle atrophy and consider the implications of these advancements in the development of new therapeutic approaches for treating GC-induced myopathy. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. Copyright © 2013 Elsevier Ltd. All rights reserved.