Lipolysis and lipophagy in lipid storage myopathies

Triglycerides droplets are massively stored in muscle in Lipid Storage Myopathies (LSM). We studied in muscle regulators of lipophagy, the expression of the transcription factor-EB (TFEB) (a master regulator of lysosomal biogenesis), and markers of autophagy which are induced by starvation and exert a transcriptional control on lipid catabolism.

We investigated the factors that regulate lipophagy in muscle biopsies from 6 patients with different types of LSM: 2 cases of riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (MADD), 1 case of primary carnitine deficiency (CD), 2 cases of neutral lipid storage myopathy (NLSD-M), 1 case of carnitine-palmitoyl-transferase-II (CPT) deficiency.

Conventional morphology and electron microscopy documented the lipid accumulation and its dramatic resolution after treatment. Muscle immunofluorescence showed that while in MADD and NLSD-M there was a co-localized expression of TFEB and p62-SQSTM1 (marker of protein aggregates) in some atrophic fibers, in CD and CPT-II deficiency the reaction was almost normal. In regenerating fibers, TFEB localized in the cytoplasm (inactive form), whereas in atrophic fibers it localized in the nuclei (active form). Lipid-accumulated/atrophic fibers did not display p62-positive protein aggregates, indicating, together with the LC3-II (marker of autophagosomes) and p62-SQSTM1 analysis, that the autophagic flux is often preserved and lipophagy occurs.

In atrophic and regenerating fibers of patients with NLSD-M we observed TFEB over-expression; in other conditions autophagy markers are increased, suggesting lipophagy active role on human lipid metabolism.