Background: Triglycerides are massively stored in LSM, i.e. carnitine deficiency, RR-MADD and NLSD-M (ATGL deficiency), conversely, in CPT-II deficiency lipid droplets are almost absent.
Objective: We aimed to analyse factors that regulate degradation and PPAR-gamma pathways. The Transcription Factor-EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is induced by starvation through an autoregulatory feedback loop and exerts a global transcriptional control on lipid catabolism via PGC1α and PPARα.
Patients and methods: We selected 6 patients with LSM: 2 RR-MADD, 1 carnitine deficiency, 2 NLSD-M, 1 CPT-II deficiency. Muscle immunofluorescence for TFEB and p62 (marker of protein aggregates) and fetal myosin (marker of regeneration) and immunoblot using p62, LC3 antibodies was done.
Results: While in 2 NLSD-M patients there was a co-localized overexpression of p62 and TFEB in some atrophic fibers, some of which were regenerating, in Carnitine and CPT-II deficiency their reaction appeared normal. In regenerating fibers TFEB localized in the cytoplasm (inactive form), whereas in atrophic fibers it localized in the nuclei (active form). Vacuolated and atrophic fibers did not display p62-positive protein aggregates, indicating, together with the LC3-II and p62 immunoblot analysis, that the autophagic flux is still preserved. Furthermore, we studied plasma myo-microRNA of 3 relatives of another NLSD-M family to observe their regulatory role in muscle. Myomicro-RNAs were inversely correlated to residual muscle mass in this NLSD-M family. Mitochondrial enzymes in two subsequent muscle biopsies of the index patient were decreased revealing an essential role of ATGL in mitochondriogenesis.
Conclusion: Nutrition and autophagy are important in RR-MADD and NLSD-M, when there is a progressive wasting of muscle.
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© 2015 Published by Elsevier Inc.
