Macroautophagy is a major intracellular, lysosome-dependent, degradative pathway that involves the formation of autophagosomes which deliver cytoplasmic contents to lysosomes for degradation ]. In both late-onset Pompe patients and KO mice, skeletal muscle GSK2118436 fibers contain large areas of undegraded autophagic material. In the KO, large pools of autophagic material are seen only in glycolytic type II muscle fibers, but not in oxidative type I fibers, which respond very well to therapy. Furthermore, in infants on ERT, a high proportion of type I fibers appears to be a good prognostic factor. Therefore, a fiber type conversion by expression of PGC1-a seemed a reasonable therapeutic approach. PGC-1a, which has recently emerged as a target of multiple physiological stimuli, is a member of the family of transcriptional cofactors of the nuclear receptor PPAR-c with a common function in the regulation of cellular energy metabolism. Multiple studies have shown that the PGC-1 family of co-activators, particularly PGC-1a, powerfully stimulates a variety of transcription factors and promotes the expression of genes involved in mitochondrial biogenesis and oxidative metabolism. Changes in PGC-1a level have been PF-04217903 implicated in the pathogenesis of obesity, diabetes, neurological disorders, and cardiomyopathy as well as in ageing. Our interest in this molecule is related to its ability to convert fast glycolytic fibers to slow oxidative fibers which have increased oxidative capacity and mitochondrial mass. We hypothesized that the fiber type conversion would make therapy-resistant type II fibers more amenable to therapy. In addition, PGC-1a has been shown to slow protein degradation in skeletal muscle and to protect muscle from atrophy caused by ageing or induced by denervation or fasting. This antiatrophic function of PGC-1a could possibly provide an additional benefit for Pompe disease, in which profound muscle wasting develops as the disease progresses. We have generated a transgenic Pompe mouse model overexpressing PGC-1a in skeletal muscle. Similar to what was reported in the wild type mice, an efficient fiber type conversion occurred in Pompe skeletal muscle. The autophagic buildup, a hallmark of Pompe disease in fast-twitch type II muscle, was no longer seen in the converted fibers, but unexpectedly, this genetic manipulation did not provide any additional therapeutic benefit. Analysis of PGC-1a transgenic Pompe mice, however, gave new insights into the pathogenesis of Pompe disease and into the role of PGC-1a in autophagosomal and lysosomal biogenesis. The experiments described in this paper were motivated by the need to improve the efficacy of enzyme replacement therapy in a metabolic myopathy, Pompe disease.