Is the limb-girdle muscular dystrophy type 2H a defective autophagy disease?

Autophagy plays an essential tissue homeostatic function by ensuring the physiological turnover of cellular components and targeting stress-damaged proteins and organelles for degradation. An important relation between defective autophagy and muscular dystrophy was recently reported in human diseases caused by collagen VI deficiency. We have recently obtained experimental evidence suggesting a novel potential link between autophagy defects and muscle dystrophy. By a protein-protein interaction screening, we found that the tripartite motif protein 32 (TRIM32), a protein whose mutation causes the limb-girdle muscular dystrophy type 2H (LGMD2H), interacts with Ambra1, a positive regulator of autophagy. Prompted by this finding, we propose to investigate whether LGMD2H is characterized by a deficit in autophagy. To this aim, we will test whether TRIM32 is able to regulate autophagy by interacting and modulating Ambra1 function. Moreover, we will assess whether the expression of TRIM32 mutants found in LGMD2H interferes with the autophagy-mediated turnover of muscle proteins. Finally, we will explore whether the induction of autophagy by pharmacological agents may counteract the increased susceptibility to cell death induction caused by TRIM32 downregulation. Altogether, these approaches will provide information on the potential application of proautophagic drugs to prevent or attenuate the progression of LGMD2H/STM diseases.