ARDC Research Link Australia

ORCID Profile
Orcid icon. 0000-0002-2705-3984

Current Organisations
Associazione Centro Dino Ferrari , Ospedale Maggiore Policlinico , Stem Cell Interdepartmental Research Centre - Università degli Studi di Milano , Università degli Studi di Milano , Ystem Srl

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Publications

Publication

Metformin rescues muscle function in BAG3 myofibrillar myopathy models

Publisher: Cold Spring Harbor Laboratory

Date: 12-03-2019

DOI: 10.1101/574806

Abstract: Dominant de novo mutations in the co-chaperone BAG3 cause a severe form of myofibrillar myopathy, exhibiting progressive muscle weakness, muscle structural failure, and protein aggregation. To identify therapies we generated two zebrafish models, one conditionally expressing BAG3 P209L and one with a nonsense mutation in bag3 . Whilst transgenic BAG3 P209L expressing fish display protein aggregation, modelling the early phase of the disease, bag3 −/− fish demonstrate impaired autophagic activity, exercise dependent fibre disintegration, and reduced swimming activity, consistent with later stages. We confirmed the presence of impaired autophagy in patient s les and screened autophagy promoting compounds for their effectiveness at removing protein aggregates, identifying nine including Metformin. Further evaluation demonstrated Metformin is not only able to remove the protein aggregates in zebrafish and human myoblasts but is also able to rescue the fibre disintegration and swimming deficit observed in the bag3 −/− fish. Therefore, repurposing Metformin provides a promising therapy for BAG3 myopathy.

Publication

Galectin‐1 Induces Skeletal Muscle Differentiation in Human Fetal Mesenchymal Stem Cells and Increases Muscle Regeneration

Publisher: Oxford University Press (OUP)

Date: 08-2006

DOI: 10.1634/STEMCELLS.2005-0564

Abstract: Cell therapy for degenerative muscle diseases such as the muscular dystrophies requires a source of cells with the capacity to participate in the formation of new muscle fibers. We investigated the myogenic potential of human fetal mesenchymal stem cells (hfMSCs) using a variety of stimuli. The use of 5-azacytidine or steroids did not produce skeletal muscle differentiation, whereas myoblast-conditioned medium resulted in only 1%-2% of hfMSCs undergoing muscle differentiation. However, in the presence of galectin-1, 66.1% +/- 5.7% of hfMSCs, but not adult bone marrow-derived mesenchymal stem cells, assumed a muscle phenotype, forming long, multinucleated fibers expressing both desmin and sarcomeric myosin via activation of muscle regulatory factors. Continuous exposure to galectin-1 resulted in more efficient muscle differentiation than pulsed exposure (62.3% vs. 39.1% p < .001). When transplanted into regenerating murine muscle, galectin-1-exposed hfMSCs formed fourfold more human muscle fibers than nonstimulated hfMSCs (p = .008), with similar results obtained in a scid/mdx dystrophic mouse model. These data suggest that hfMSCs readily undergo muscle differentiation in response to galectin-1 through a stepwise progression similar to that which occurs during embryonic myogenesis. The high degree of myogenic conversion achieved by this method has relevance for the development of therapies for muscular dystrophies.