Evaluation of cyclin D3 as a potential target to remodel dystrophic muscle toward the slow, oxidative phenotype (DSB.AD004.296)

Area tematica

Scienze biomediche

Area progettuale

Struttura responsabile del progetto di ricerca

Istituto di Biochimica e Biologia Cellulare (IBBC)

Responsabile di progetto

MAURIZIA CARUSO
Telefono: 0690091478
E-mail: maurizia.caruso@cnr.it

Abstract

It has long been known that slower, oxidative muscle fibers in patients with Duchenne Muscular Dystrophy (DMD) are more resistant to the dystrophic pathology in comparison with faster, more glycolytic fibers.
We have previously shown that mice lacking cyclin D3 display an increased number of myofibers with high oxidative capacity, enhanced running endurance and increased energy expenditure and fatty acid oxidation.
The objective of this proposal is to evaluate whether inactivation of cyclin D3 in the mdx mouse model of DMD can attenuate the dystrophic pathology by promoting a slower, more oxidative muscle phenotype.
To this aim, cyclinD3-/- mice will be crossed with mdx mice and several parameters that characterize the dystrophic process will be analyzed, including extent of myofiber damage, inflammatory process, muscle regeneration, fibrosis. Muscle performance will be evaluated by submitting mice to exhaustion treadmill assays and by assessing the contractile activity of muscles in vitro. Furthermore, we will evaluate the effect of inhibition of cyclin D3 expression or inhibition of the associated CDK4 kinase activity in adult mdx mice.

Obiettivi

Based on our previous studies showing a shift toward a slower fiber type in cyclinD3-/- skeletal muscle, and taking into account the knowledge that an increase of oxidative program can beneficially alter the phenotype of dystrophic skeletal muscle, we will ask whether inactivation of cyclin D3 can yield benefit to the dystrophic pathology.
Specifically we plan to:
AIM1 - Characterize the dystrophic phenotype of mdx mice carrying an inactivating mutation in the cyclinD3 coding gene.
AIM2 - Evaluate the effects of an inhibition of cyclin D3 in postnatal mdx mice. This will be addressed trough shRNA-mediated knockdown of cyclin D3 or through pharmacological inhibition of the cyclin D3-associated CDK4 activity.
The achievement of these tasks will give indications as to whether inhibition of cyclin D3 may provide a therapeutic strategy to improve pathology in dystrophic patients.

Data inizio attività

20/04/2020

Parole chiave

Muscular dystrophy, muscle fibers, metabolism

Ultimo aggiornamento: 04/05/2024