1. Skeletal muscle regenerative decline with aging: causes and potential reversal

Background and hypothesis:

Skeletal muscle regenerative capacity declines with aging, particularly at very advanced geriatric age, during sarcopenia. We have shown that geriatric muscle stem cells (satellite cells) lose their normal quiescent state and undergo a quiescence-to-senescence switch, which irreversibly impedes muscle regeneration. We have recently shown dysregulated autophagy in quiescent satellite cells with aging. We hope to demonstrate that the muscle stem cell functional decline, provoked by senescence entry at the expense of the homeostatic quiescence state, accounts for the loss of regenerative capacity of skeletal muscle with aging, and that loss of autophagy is causally implicated.


1. Analysis of autophagy in aging muscle stem cells and relationship with defective regeneration.

2. Analysis of FoxO and p38 MAPK signaling in aging muscle stem cells and relationship with senescence entry and defective muscle regeneration.

3. Analysis of the impact of nutritional regimes on stem cell rejuvenation in aging muscle: consequences on tissue regeneration and on sarcopenia.

2. Inflammation and fibrosis in muscle regeneration: implications for Duchenne muscular dystrophy progression. 

Background and hypothesis:

Fibrosis, essentially an excessive accumulation of extracellular matrix (ECM) components, particularly collagen, increases with age in Duchenne Muscular Dystrophy (DMD) patients and enhances disease severity, but the underlying fibrogenic mechanisms are still unknown.  We recently found that: i) inflammation promotes fibrosis in the mdx mouse model of DMD, with a potential implication of alternatively activated (aa) macrophages; ii) myofibroblasts (collagen producing cells) are increased in dystrophic muscle; iii) an implication of microRNA-21 (miR-21) in muscle fibrogenesis. We hope to prove using mouse transgenesis the implication of these mechanisms in fibrosis development in DMD.


1. Genetic demonstration of the role of the aa macrophage response (and other myeloid cells) in dystrophic muscle fibrosis.

2. Genetic tracing analysis to demonstrate the cellular origin of myofibroblasts (i.e. fibrosis).

3. Genetic dissection of the relative function of miR-21 in myeloid and fibroblast cell types in dystrophic muscle, and its contribution to fibrosis.