Rapamycin nanoparticles target defective autophagy in muscular dystrophy to enhance both strength and cardiac function

Abstract

Duchenne muscular dystrophy in boys progresses rapidly to severe impairment of muscle function and death in the second or third decade of life. Current supportive therapy with corticosteroids results in a modest increase in strength as a consequence of a general reduction in inflammation, albeit with potential untoward long-term side effects and ultimate failure of the agent to maintain strength. Here, we demonstrate that alternative approaches that rescue defective autophagy in mdx mice, a model of Duchenne muscular dystrophy, with the use of rapamycin-loaded nanoparticles induce a reproducible increase in both skeletal muscle strength and cardiac contractile performance that is not achievable with conventional oral rapamycin, even in pharmacological doses. This increase in physical performance occurs in both young and adult mice, and, surprisingly, even in aged wild-type mice, which sets the stage for consideration of systemic therapies to facilitate improved cell function by autophagic disposal of toxic byproducts of cell death and regeneration.

Autophagy regulates satellite cell ability to regenerate normal and dystrophic muscles

“…Other studies demonstrates that the E3 ubiquitin ligase TNF receptor-associated factor 6 (TRAF6), which regulates autophagy, displays a stage-dependent effect in mdx mice, 25 further supporting the notion that unbalanced autophagy occurs in DMD. Defective autophagy of mdx animals is restored by rapamycin delivery through nanoparticles 45 and Simvastin treatment that reduces ROS by enhancing the autophagic process 27,46 leading to improved physical performance.…”

Internalization and fate of silica nanoparticles in C2C12 skeletal muscle cells: evidence of a beneficial effect on myoblast fusion

“…18 Notably, rapamycin, an autophagy-inducing compound successfully delivered using nanoparticle formulation, enhanced physical performance. 19 There is an emerging field of nanoparticle therapeutics for muscle disorders and, potentially, muscle repair. For instance, the differentiation of myoblasts has been stimulated with the use of silica nanoparticles loaded with γ-secretase inhibitors, blocking the Notch signaling pathway.…”

m-TOR Inhibitors in the Current Practice

“…This increase in physical performance occurs in both young and adult mice, and, surprisingly, even in aged wild-type mice. Although the exact mechanism responsible for rapamycin's entry into muscle tissue remains to be clarified, the effect on autophagy is clear and seems dependent on NP-linked depot delivery, because oral therapy is ineffective at the doses that were administered [71,72].…”