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 Huntington's 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.