What can embryonic development tell us about disease mechanisms? The case of skeletal muscle.

Sólveig Thorsteinsdóttir
Group Leader, Development and Evolutionary Morphogenesis Group

Skeletal muscle development starts early in the development of vertebrate embryos and progressively builds the skeletal muscles that make us able to move and breathe. Throughout most of our lives, skeletal muscle is a tissue with remarkable regenerative potential because it contains muscle stem cells, derived from embryonic muscle progenitor cells, which are tucked into a specific “niche” near the existing muscle fibres. When muscles are damaged, some of these cells turn on the muscle developmental programme and repair the damaged muscle fibres.
Congenital muscular dystrophies are diseases where the connection between the muscle fibres and the extracellular matrix molecule laminin 211 (which normally surrounds muscle fibres) is faulty, leading to muscle weakness evident already at birth. Among the most severe ones is LAMA2-congenital muscular dystrophy (LAMA2-CMD) where laminin 211 is absent. Muscle damage and wasting starts early in life and patients rarely survive past their teens or early twenties. There is no treatment or cure.
Since infants with LAMA2-CMD are already affected at birth, the defect underlying the disease must have arisen during development in utero. Here we used a mouse model for LAMA2-CMD to study when, during embryonic development, this disease starts to manifest itself and exactly what mechanisms of muscle development and/or maintenance are the first to go wrong.
We find perturbations in two periods of skeletal muscle development in laminin 211-deficient mouse embryos, the most dramatic one being during the later stages of in utero development. We see an impaired growth of the muscles concomitantly with a dramatic loss in the number of muscle progenitor cells, but no increase in cell death. Analysis of markers of myogenesis indicate that the absence of laminin 211 leads to precocious differentiation of muscle progenitor cells. Thus laminin 211-deficient mice are not only born with smaller muscles than their normal littermates, but their muscles also have fewer muscle progenitor cells available for muscle growth and repair.
These results are the first to describe defects in laminin 211-deficient mouse muscles before birth. Understanding the molecular mechanisms underlying the loss of progenitor cells in these muscles during development may help develop early intervention therapies which may one day increase the lifespan, improve clinical outcomes and quality of life for LAMA2-CMD patients.

5ª feira, 19 de Novembro de 2015
FCUL (Edif. C6) – 12.00h-13.00h – Sala 6.2.51