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Limb Girdle musclular dystrophy: a connection defect in the generation of mitochondria 20-12-2016

In a study published in Cell Reports researchers of the University of Milan demonstrate the importance of homeostasis in mitochondrial muscular dystrophy, identifying the possibility of additional treatment options to the classic therapy with corticosteroids.

researcher in the labThe ability to generate mitochondria in a process called mitochondrial biogenesis is an important compensatory mechanism to respond to changing bioenergetic needs, for example in cold adaptation or, in the case of skeletal muscle, exercise, bringing about rearrangements in tissue molecular structure and bioenergetics.

In the work just published in Cell Reports, the group of researchers coordinated by Emilio Clementi and Clara De Palma of the Department of Biomedical and Clinical Sciences "L. Sacco" - University of Milan - and  Fatebenefratelli-Sacco Hospital, in collaboration with the Eugenio Medea Scientific Institute and IRCCS Santa Lucia (Roma)  has identified a link between a type of limb girdle muscular dystrophy, the type 2 Limb Girdle muscular Dystrophy (LGMD-2D), and a defect in the process of mitochondrial biogenesis.

This defect was found to be associated with a numbers of mitochondria and an overall oxidative capacity (energy) of the muscle reduced with respect to heatlhy persons.

Furthermore the researchers have investigated at the preclinical level the effect, on this mitochondrial biogenetic defect, of drug manipulation of an enzyme (an histone deacetylase, with trichostatin A) and a transcription factor (PGC-1a, with nitric oxide).

Both approaches led to functional improvement of skeletal muscle while acting with different mechanisms. Trichostatin A changes the assembly of chromatin at the level of the promoter of PGC-1a increasing its levels of expression and restoring the process of mitochondrial biogenesis; this involves an increase in the number of mitochondria and oxidative fibres within the muscle. Nitric oxide reduces the level of acetylation of PGC-1a without changing its expression levels; this increases the fatty acids oxidation and significantly improves the oxidative capacity of the muscle.

These data demonstrate the importance of mitochondrial homeostasis in muscular dystrophy and how its modulation may represent an interesting novel therapeutic option able to impact directly on the dystrophic muscle. This result is of particular interest in limb girdle muscular dystrophy as a possible alternative to the classical therapy with corticosteroids, or as a support to it.

For more information
The University of Milan
Department of Biomedical and Clinical Sciences "L. Sacco"
Prof. Emilio Clementi