Defining the role of skeletal muscle peroxisomes in Zellweger Spectrum Disorders

Zellweger Spectrum Disorders (ZSD) are rare hereditary diseases that occur when peroxisomes are missing or do not function properly. Mutations in Pex genes cause a defective formation of peroxisomes.
Since peroxisomes are critical for essential metabolic functions, their dysfunction causes damage to several body organs. ZSD includes craniofacial alterations, brain, kidney, and liver dysfunction. Because there is no effective cure for ZSD, a better understanding of the mechanisms involved in ZSD is necessary. Skeletal muscle is severely affected in ZSD, probably contributing to muscle tone loss, movement, sucking or swallowing difficulties, and respiratory problems. Skeletal muscle, the largest tissue of our body, has a critical role in whole-body metabolism. However, the role of skeletal muscle in ZSD progression has never been investigated. Thus, we hypothesize that peroxisomal dysfunction in skeletal muscle contributes to ZSD metabolic alterations and disease progression. To test our hypothesis, we will use a mouse model, unable to assemble functional peroxisomes, exclusively in skeletal muscle. We propose studying the consequences of peroxisomal dysfunction in skeletal muscle by investigating: 1) how peroxisomes and mitochondria, affect one another, and the impact on muscle metabolism and 2) how peroxisomal loss affects muscle mass, force and the interaction between muscles and nerves. Finally, to confirm the validity of our study, our mice findings will be assessed in human ZSD samples.Our results could constitute the basis for investigating therapies and lifestyle interventions to improve muscle function and patients’ quality of life.