Transcriptomic analysis of skeletal muscle from CAG-BAG3P209L-mice
Myofibrillar myopathy-6 (MFM6) is a rare, autosomal dominant neuromuscular disease that is characterised by devastating generalized and proximal muscle weakness that progresses rapidly in childhood, restrictive cardiomyopathy, and respiratory insufficiency. MFM6 is caused by single base mutation in the gene encoding the co-chaperone BAG3, resulting in a single amino acid exchange (P209L) in the protein. We have focused on the severe skeletal muscle phenotype using a humanized mouse model, in which a fusion protein consisting of the human BAG3P209L and the green fluorescent protein is overexpressed. Transgenic mice displayed decreased body weight and severe skeletal muscle weakness a few weeks after birth. Skeletal muscle function of CAG-BAG3P209L-mice, such as maximal force development, was strongly impaired and sarcomere disintegration with massive inflammation, protein aggregate formation, and increased number of centralized nuclei mimicking the human pathology was observed. Proteomics and transcriptomics analysis demonstrated an increase in protein synthesis, blocked autophagy, loss of sarcomere proteins, and impaired mitophagy.