Summary Skeletal muscle has the remarkable ability to modulate its mass in response to changes in nutritional input, functional utilization, systemic disease, and age. This is achieved by the coordination of transcriptional and post-transcriptional networks and the signaling cascades balancing anabolic and catabolic processes with energy and nutrient availability. The extent to which alternative splicing regulates these signaling networks is uncertain. Here we investigate the role of the RNA-binding protein hnRNP-U on the expression and splicing of genes and the signaling processes regulating skeletal muscle hypertrophic growth. Muscle-specific Hnrnpu knockout (mKO) mice develop an adult-onset myopathy characterized by the selective atrophy of glycolytic muscle, the constitutive activation of Akt, increases in cellular and metabolic stress gene expression, and changes in the expression and splicing of metabolic and signal transduction genes. These findings link Hnrnpu with the balance between anabolic signaling, cellular and metabolic stress, and physiological growth.

Skeletal muscle has the remarkable ability to modulate its mass in response to physiological changes associated with nutritional input, functional utilization, systemic disease, and age. A decreased responsiveness to anabolic stimuli is thought to contribute significantly to the loss of skeletal muscle mass and strength associated with sarcopenia, however the molecular mechanisms precipitating this are unclear. The signal transduction pathways that control the relative balance between anabolic and catabolic processes are tightly regulated at the transcriptional and post-transcriptional levels. Alternative splicing produces multiple protein isoforms from a single gene in a cell-type-specific manner and in response to environmental cues. We show that sustained activation of Akt1 in Hnrnpu deficient mice leads to premature muscle wasting, in part, through impaired autophagy while providing mechanistic insights into the development of anabolic resistance.3 Introduction: