Out FoxO'd by microRNA. Focus on "miR-182 attenuates atrophy-related gene expression by targeting FoxO3 in skeletal muscle".

OVER THE PAST FEW YEARS, non-coding RNAs (ncRNAs) have emerged as important regulators of gene expression (2). A family of small ncRNAs, known as microRNAs (miRNAs), have been shown to have a role in a wide range of developmental and cellular processes as well as certain pathologies such as cancer. This family of ncRNAs functions through a posttranscriptional mechanism by inhibiting mRNA translation and/or degradation of a target transcript. The discovery that miRNAs were present in a wide range of animals also revealed that some miRNAs were in fact expressed in a tissue-specific manner; for example, the expression of the mature miRNA (miR) miR-1 was found to be restricted to the heart, with later studies showing miR-1 expression in skeletal muscle as well (9). Since then, a small family of muscle-specific miRNAs, referred to as myomiRs, have been identified and shown to have a central role in myogenesis and adaptation to both physiological and pathological stresses (7). The finding that miRNAs might mediate skeletal muscle plasticity is not surprising given the general consensus in the field that miRNAs are involved in mediating the stress response of the cell, helping to maintain and restore cellular homeostasis through the regulation of gene expression (3). In recent years, evidence has emerged that both myomiRs and more broadly expressed miRNAs are involved in the regulation of skeletal muscle metabolism, fiber type, and mass (7). In particular, great strides have been made in understanding how miRNAs impact the regulatory networks that underlie skeletal muscle atrophy in response to catabolic stimuli. The muscle-specific E3 ubiquitin ligases, MAFbx/atrogin-1 and muscle RING-finger 1 (MuRF-1), are master regulators of skeletal muscle atrophy by increasing cellular protein degradation via targeting proteins for the ubiquitin-proteasome system (5). The finding that the forkhead box O3 (FoxO3) transcription factor promotes expression of MAFbx/atrogin-1 and MuRF-1, as well as genes involved in autophagic/lysosomal proteolysis, provided a unifying mechanism for coordinating the regulation of protein degradation that underlies muscle atrophy (10, 15). Wada and colleagues (14) provided the first Address for reprint requests and other correspondence: J. J. McCarthy, Dept. of Physiology, Univ. of Kentucky, 800 Rose St., Lexington, KY 40536-0298 (e-mail: [email protected]).