MicroRNAs modulated by local mIGF-1 expression in mdx dystrophic mice

Abstract

Duchenne muscular dystrophy (DMD) is a X-linked genetic disease in which the absence of dystrophin leads to progressive lethal skeletal muscle degeneration. It has been demonstrated that among genes which are important for proper muscle development and function, micro-RNAs (miRNAs) play a crucial role. Moreover, altered levels of miRNAs were found in several muscular disorders, including DMD. A specific group of miRNAs, whose expression depends on dystrophin levels and whose deregulation explains several DMD pathogenetic traits, has been identified. Here, we addressed whether the anabolic activity of mIGF-1 on dystrophic muscle is associated with modulation of microRNAs expression. We demonstrated that some microRNAs are strictly linked to the dystrophin expression and are not modulated by mIGF-1 expression. In contrast, local expression of mIGF-1 promotes the modulation of other microRNAs, such as miR-206 and miR-24, along with the modulation of muscle specific genes, which are associated with maturation of regenerating fibers and with the stabilization of the differentiated muscle phenotype. These data suggest that mIGF-1, modifying the expression of some of the active players of muscle homeostasis, is able, even in absence of dystrophin expression, to activate circuitries that confer robustness to dystrophic muscle.

Stem cells and tissue niche: two faces of the same coin of muscle regeneration

“…In addition we recently demonstrated that muscle-specific expression of mIGF-1 can counter aspects of the muscular dystrophy associated with the loss of dystrophin, modulating relevant molecules of the genetic and epigenetic circuitries in the mdx dystrophic mouse model. 45 Our work is consistent with a model in which overexpression of mIGF-1 confers robustness to dystrophic muscle, impedes the activation of a chronic inflammatory response, activates the circuitry of muscle differentiation and maturation. This results in a functional homeostatic maintenance of dystrophic muscle.…”

“…This results in a functional homeostatic maintenance of dystrophic muscle. 45 Another study also demonstrated that co-injection of the rAAV-microdystrophin and rAAV-mIGF-1 vectors resulted in increased muscle mass and strength, reduced myofiber degeneration, and increased protection against contraction-induced injury. 46 These results suggest that a combination of promoting muscle regenerative capacity and preventing muscle necrosis could be an effective treatment for the secondary symptoms caused by the primary loss of dystrophin.…”

Overexpression of miR-210 and its significance in ischemic tissue damage

“…Necrotic cell death stimulates a host inflammatory response involving the recruitment of specific myeloid cell populations 29 . To further confirm the differences observed in tissue damage among the three groups of mice, the presence of neutrophil granulocytes was investigated.…”

“…To further strengthen our data, the presence of inflammatory cells in the ischemic tissues was also evaluated. Indeed, necrotic cell death stimulates a host inflammatory response that involves the recruitment of specific myeloid cell populations within the injured area 29 . Specifically, neutrophils represent the first inflammatory myeloid cells that invade the area of injury with a peak of expression from 1 day to 5-day post-injury 30 , 31 .…”

Noncoding RNAs and Duchenne Muscular Dystrophy

“…The distribution of miRNAs in mouse muscle is better understood, compared to the human counterpart, with distinct patterns having been observed in the tibialis anterior (TA) muscle [31], diaphragm [37], heart [38], and the soleus and plantaris muscles in the leg [37]. miR-206 is particularly important in MDX mice, as it has been shown to be induced by fibro-adipogenic progenitors (FAPs), which are known to contribute to the pathogenesis and progression of DMD [39], as well as being modulated by mouse insulin-like growth factors (mIGF-1) [40]. -1, -21, -31, -133, -142-3p, -149-5p, -193b, -206, and -378a-3p) for the evaluation of therapeutic outcome in medical approaches for numerous muscular dystrophies, including DMD [48].…”