Abstract
PGC-1α is a transcriptional co-activator that plays a central role in the regulation of energy metabolism. Our interest in this protein was driven by its ability to promote muscle remodeling. Conversion from fast glycolytic to slow oxidative fibers seemed a promising therapeutic approach in Pompe disease, a severe myopathy caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA) which is responsible for the degradation of glycogen. The recently approved enzyme replacement therapy (ERT) has only a partial effect in skeletal muscle. In our Pompe mouse model (KO), the poor muscle response is seen in fast but not in slow muscle and is associated with massive accumulation of autophagic debris and ineffective autophagy. In an attempt to turn the therapy-resistant fibers into fibers amenable to therapy, we made transgenic KO mice expressing PGC-1α in muscle (tgKO). The successful switch from fast to slow fibers prevented the formation of autophagic buildup in the converted fibers, but PGC-1α failed to improve the clearance of glycogen by ERT. This outcome is likely explained by an unexpected dramatic increase in muscle glycogen load to levels much closer to those observed in patients, in particular infants, with the disease. We have also found a remarkable rise in the number of lysosomes and autophagosomes in the tgKO compared to the KO. These data point to the role of PGC-1α in muscle glucose metabolism and its possible role as a master regulator for organelle biogenesis - not only for mitochondria but also for lysosomes and autophagosomes. These findings may have implications for therapy of lysosomal diseases and other disorders with altered autophagy.
Highlights
Pompe disease is a rare genetic disorder that affects individuals at any age [1]
We have previously shown that the autophagic buildup in muscles from knockout mice (KO) mice is caused by a combination of increased production of autophagosomes and their inefficient resolution by lysosomes, leading to the accumulation of autophagic substrates ubiquitinated (Ub)-proteins [22]
It has been previously shown that PGC-1a is not the only determinant of the fiber type: a significant number of type I and IIa fibers still remained in muscle-specific PGC-1a - knockout mice [23]
Summary
Pompe disease (glycogen storage disease type II) is a rare genetic disorder that affects individuals at any age [1]. It is caused by deficiency of the enzyme acid alpha-glucosidase (GAA), which is essential for the degradation of glycogen to glucose in the acidic environment of the lysosomes. The disease manifests with a broad clinical spectrum ranging from the severe rapidly progressive infantile form to milder late-onset variants [1,2,3]. In the late-onset forms, caused by a partial enzyme deficiency, cardiac muscle is spared, but slowly progressive skeletal muscle weakness leads to wheelchair and ventilator dependence, and premature death from respiratory insufficiency [3]
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