RESEARCH & DISCOVERIES

Using molecular and cell biology techniques and innovative mouse models, our current research focuses on developping novel treatments for Duchenne Muscular Dystrophy and Cancer Cachexia.  Keep reading to find out what we are currently investigating.

Molecule

TRANSCRIPTIONAL MECHANISMS REGULATING MUSCLE STEM CELL FATE

We discovered that CCAAT/Enhancer Binding Protein beta (C/EBPβ) expression in healthy muscle is restricted to SCs and is rapidly downregulated upon induction to differentiate. Forced expression of C/EBPβ in myoblasts blocks differentiation, while loss of C/EBPβ in SCs results in precocious differentiation in culture, muscle fiber hypertrophy in vivo and enhanced repair after a single injury (Marchildon et al, Stem Cells 2012 30:2619-30). Overexpression of C/EBPβ in myoblasts increased the number of non-cycling Pax7+ cells whereas in the absence of C/EBPβ, satellite cells fail to generate reserve cells in culture. In vivo, C/EBPβ knockdown leads to progressive loss of satellite cells and regenerative potential (Lala-Tabbert et al, Skeletal Muscle 2016 Dec 7;6(1):40). In cancer cachexia, an expansion of the SC population without appropriate regenerative responses is observed. We found that in cachexia C/EBPβ levels are increased in SCs cells leading to a blockade of differentiation and muscle repair and contribute directly to muscle wasting (Marchildon et al. PLOS One 2015 10(12):e0145583, and Marchildon et al. Cell Death Dis 2016 7:e2109).

Microscope

IMPROVING STEM CELL-BASED THERAPIES FOR DUCHENNE MUSCULAR DYSTROPHY

We used the phosphodiesterase inhibitor IBMX to transiently induce C/EBPβ expression in freshly isolated primary myoblasts to restrain activation in culture. IBMX treatment promoted satellite cell marker expression in a largely C/EBPβ-dependent fashion, and culture expansion. Once transplanted into dystrophic muscle, IBMX-treated cells contributed more efficiently to muscle repair with improved dystrophin expression, better migration from the injection site and better survival than controls. Further, IBMX-treated cells were able to repopulate the satellite cell niche, suggesting potential for long term sustained repair. This work was published as Lala-Tabbert et al, in Stem Cells Transl Med 2016 Apr;5(4):500-10.

Scientist in the Lab

REGULATION OF MYOGENIC DIFFERENTIATION BY NUCLEAR HORMONE RECEPTORS

While TGFβ is a potent inhibitor of myogenesis, we recently demonstrated that the TGFβ effector protein SMAD2, in the absence of TGFβ, is required for myogenic differentiation and muscle repair after injury (Lamarche et al., Development, 2021, Research Highlight and Cover art). We have also explored the crosstalk between the TGFβ pathway and retinoic acid receptor signalling. Using genetic models, we demonstrated that retinoic acid antagonizes TGFβ by decreasing SMAD2 activation and stimulating SMAD3 expression, which in turn interferes with C/EBPβ occupancy of the Pax7 promoter, enhancing myogenesis. These findings were published in Lamarche et al. Skeletal Muscle 2015.

Microscope

UNCOVERING MECHANISMS DRIVING CANCER CACHEXIA

In cancer cachexia, we found that muscle repair was inhibited and this correlated with an expansion of the SC population that expressed C/EBPβ. Persistent C/EBPβ levels in SCs cells blocked differentiation and muscle repair and contribute directly to muscle wasting (Marchildon et al. PLOS One 2015, and Marchildon et al. Cell Death Dis 2016). This was foundational in developping in culture and animal models of cachexia and for identifying the role for C/EBPβ in the tumour.