Reactivation of autophagy by spermidine ameliorates the myopathic defects of collagen VI-null mice

Abstract

Autophagy is a self-degradative process responsible for the clearance of damaged or unnecessary cellular components. We have previously found that persistence of dysfunctional organelles due to autophagy failure is a key event in the pathogenesis of COL6/collagen VI-related myopathies, and have demonstrated that reactivation of a proper autophagic flux rescues the muscle defects of Col6a1-null (col6a1^−/−) mice. Here we show that treatment with spermidine, a naturally occurring nontoxic autophagy inducer, is beneficial for col6a1^−/− mice. Systemic administration of spermidine in col6a1^−/− mice reactivated autophagy in a dose-dependent manner, leading to a concurrent amelioration of the histological and ultrastructural muscle defects. The beneficial effects of spermidine, together with its being easy to administer and the lack of overt side effects, open the field for the design of novel nutraceutical strategies for the treatment of muscle diseases characterized by autophagy impairment.

Keywords:

• autophagy
• collagen VI
• muscular dystrophies
• skeletal muscle
• spermidine

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

We gratefully thank Prof. Noboru Mizushima for providing us with GFP-LC3 reporter mice. Moreover, we are sincerely grateful to Roberto Costa, Andrea Armani, Enrico Moro and Marco Sandri for providing us advice and help.

Supplemental Material

Supplemental data for this article can be accessed on the publisher's website.

Funding

This work was supported by Telethon Foundation (Grants GGP10225 and GGP14202) and by the Italian Ministry of University and Research (FIRB Accordo di Programma RBAP11Z3YA_003).