Defective Muscle Mitochondrial Biogenesis in Spinal Muscular Atrophy. (P7.004)

OBJECTIVE: To investigate mitochondrial dysfunction in muscle biopsies from patients presenting Spinal Muscular Atrophy (SMA), a pediatric genetic disorder featuring the degeneration of motor neurons, skeletal muscle weakness and atrophy due to SMN mutations. BACKGROUND: The repression of mitochondrial biogenesis has been postulated to be a major mechanism underlining neurodegenerative disorders such as Huntington9s disease (HD) and Amyotrophic Lateral Sclerosis (ALS). Indeed, the genetic or pharmacological up-regulation of PGC1-alpha, the main cofactor of mitochondrial biogenesis, resulted in phenotype and lifespan improvements in murine models of HD, ALS as well as primary mitochondrial encephalomyopathies. These findings suggest a potential way of intervention, translatable to other disorders. METHODS: We studied muscle samples from 24 genetically proven SMA patients (type I: 9, type II: 8, type III: 7) at histochemical, biochemical and molecular levels. RESULTS: Histochemical cytochrome c oxidase (COX) deficiency was evident in all subjects with COX-deficient area higher than 51% of the section. Residual activities of the respiratory chain complexes I (41.3%), II (26.6%) and IV (30.7%) were severely impaired in SMA (n=8), compared to controls (n=7). We demonstrated a massive reduction of mitochondrial DNA content (mean value >70%) even affecting different muscles from the same patient. We linked these alterations to the down regulation of PGC1-alpha (13% of control levels) and its downstream targets including transcription factors NRF1 (37%), NRF2 (43%) and TFAM (35%) by custom array gene expression studies. We also observed that SMA severity positively correlated with the extent of these abnormalities. We are performing wide spectrum analysis to find which PGC1-dependant pathway is more deregulated in SMA and to extend these findings to human cells and animal models. DISCUSSION: Here we demonstrate that mitochondrial content and PGC-1a expression are significantly reduced in SMA muscles. Therapeutic strategies aiming to counteract these changes might reveal beneficial for SMA patients. Disclosure: Dr. Ronchi has nothing to disclose. Dr. Ripolone has nothing to disclose. Dr. Barca has nothing to disclose. Dr. Berardinelli has nothing to disclose. Dr. Morandi has nothing to disclose. Dr. Mora has nothing to disclose. Dr. Bordoni has nothing to disclose. Dr. Fortunato has nothing to disclose. Dr. Fagiolari has nothing to disclose. Dr. Violano has nothing to disclose. Dr. Vallejo has nothing to disclose. Dr. Corti has nothing to disclose. Dr. Toscano has nothing to disclose. Dr. Sciacco has nothing to disclose. Dr. DiMauro has received personal compensation in an editorial capacity for MedLink Neurology. Dr. Comi has nothing to disclose. Dr. Moggio has nothing to disclose.