Laboratoire Matière et Systèmes Complexes

(Séminaire initialement prévu le 13 juin, reporté au 22 juin).

Alessandra Pincini :

Role of Serum Response Factor as a mediator of mechanotransduction in skeletal muscle

While significant progress has been made in understanding the signaling pathways that modulate muscle mass, the molecules that translate mechanical cues into signals that support hypertrophy/atrophy are unclear.

The transcription factor Srf (Serum Response Factor) was identified as a new factor controlling muscle mass in response to workload (Guerci et al., 2012). SRF-dependent gene transcription is modulated by coactivators, including the myocardin-related transcription factor Mrtf-A (Miralles et al 2003, Wang et al, 2002). SRF/Mrtf-A-dependent gene transcription is induced when MRTF-A localizes to the nucleus where it is able to form complexes with SRF, resulting in transcription of genes that contain promoter elements that bind the SRF/Mrtf-A complex (Posern and Treisman 2006). Recent studies have shown that Mrtf-A localization is regulated by actin dynamics in the nucleus (Baarlink et al., 2013 and Vartiainen et al., 2007). G-actin in the nucleus binds to Mrtf-A, enabling it to be exported to the cytosol (Vartiainen et al., 2007). Thus, high levels of G-actin in the nucleus seen during serum deprivation lead to low levels of nuclear Mrtf-A. G-actin levels in the nucleus can be regulated by both F-actin polymerisation in the cytosol and in the nuclei (Baarlink et al., 2013). Moreover the atypical actin regulatory protein MICAL-2 affects nuclear actin. MICAL-2 is an enzyme that binds to F-actin and trigger its depolymerization through a redox modification of actin. Its expression reduces nuclear G-actin, resulting in Mrtf-A translocation and subsequent activation of SRF target genes transcription (Lundquist et al., 2014).

In in vivo studies, using a mouse model of conditional and inducible deletion of Srf within adult myofibers, we have shown that Srf loss leads to blunted overload-induced muscle hypertrophy (Guerci et al, 2012) and to increased denervation-induced atrophy, a situation of “mechanical silencing” of the muscle (Collard et al, 2014). We have demonstrated that the actin–Mrtf–Srf pathway is specifically downregulated in the muscle atrophy that is induced through disuse in mice. We showed that the abolition of mechanical signals leads to the rapid accumulation of G-actin in myonuclei and the export of the Srf coactivator Mrtf-A, resulting in a decrease of Mrtf–Srf-dependent transcription that contributes to atrophy.

These results highlight Srf as a crucial mediator of mechanotransduction in skeletal muscle tissue and a key transcription factor regulating skeletal muscle mass as a function of mechanical activity.

Ana Espinosa :

Magneto-photo-thermal modality as an efficient approach for tumor treatment

New multifunctional nanomaterials that combine different therapeutic capabilities in one-single object are attracting increasing attention in cancer battle.1 Nanostructures which couple magnetic and plasmonic properties have demonstrated a synergistic therapeutic and diagnostic potential: iron oxide cores (magnetic) bring potential for magnetic resonance imaging (MRI), magnetic manipulation and targeting, while gold layers (plasmonic) were integrated to provide optical response of the hybrids for imaging or photothermal heating. However, nanomaterials that incorporate the simultaneous action of magnetism and light to efficiently deliver heating to induce tumour cell death (hyperthermia) are rare. Here, we explore a new bimodal approach, magneto-photo-thermia, through two examples of nanostructures devoted to thermal-therapies: i) magnetic-plasmonic nanohybrids (composed of a core optimized for high efficiency in magnetic hyperthermia, and a gold shell with tunable plasmonic properties from the visible to the near infrared region (NIR)2 and ii) iron oxide cube-shaped nanomaterials (Figure 1).3 Efficient and amplified heat conversion was achieved for both cases, either in suspension till in vivo conditions, becoming into a new dual hyperthermic-modality for tumor treatment with minimal collateral tissue damage.

References: 1. Di Corato R, et al. (2015), Combining magnetic hyperthermia and photodynamic therapy for tumor ablation with photoresponsive magnetic liposomes. ACS Nano 9, 2904-2916. 2. A. Espinosa, et al. (2015), Can magneto-plasmonic nanohybrids efficiently combine photothermia with magnetic hyperthermia?. Nanoscale 7, 18872-18877. 3. A. Espinosa, et al. (2016), The duality of iron oxide nanoparticles in cancer therapy: amplification of the heating efficiency by magnetic hyperthermia and photothermal bimodal treatment. ACS Nano 10, 2436–2446.