Skeletal muscle hypertrophy and regeneration are important adaptive responses to both physical activity and pathological stimuli. Failure to maintain these processes underlies the loss of skeletal muscle mass and strength that occurs with ageing and in myopathies. Here we show that stable expression of a gene encoding insulin-like growth factor 1 (IGF-1) in C2C12 skeletal muscle cells, or treatment of these cells with recombinant IGF-1 or with insulin and dexamethasone, results in hypertrophy of differentiated myotubes and a switch to glycolytic metabolism. Treatment with IGF-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the Ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor NF-ATc1. Hypertrophy is suppressed by the calcineurin inhibitors cyclosporin A or FK506, but not by inhibitors of the MAP-kinase or phosphatidylinositol-3-OH kinase pathways. Injecting rat latissimus dorsi muscle with a plasmid encoding IGF-1 also activates calcineurin, mobilizes satellite cells and causes a switch to glycolytic metabolism. We propose that growth-factor-induced skeletal-muscle hypertrophy and changes in myofibre phenotype are mediated by calcium mobilization and are critically regulated by the calcineurin/NF-ATc1 signalling pathway.

We have isolated a murine cDNA encoding a 9-kD protein, Chisel (Csl), in a screen for transcriptional targets of the cardiac homeodomain factor Nkx2-5. Csl transcripts were detected in atria and ventricles of the heart and in all skeletal muscles and smooth muscles of the stomach and pulmonary veins. Csl protein was distributed throughout the cytoplasm in fetal muscles, although costameric and M-line localization to the muscle cytoskeleton became obvious after further maturation. Targeted disruption of Csl showed no overt muscle phenotype. However, ectopic expression in C2C12 myoblasts induced formation of lamellipodia in which Csl protein became tethered to membrane ruffles. Migration of these cells was retarded in a monolayer wound repair assay. Csl-expressing myoblasts differentiated and fused normally, although in the presence of insulin-like growth factor (IGF)-1 they showed dramatically enhanced fusion, leading to formation of large dysmorphogenic “myosacs.” The activities of transcription factors nuclear factor of activated T cells (NFAT) and myocyte enhancer–binding factor (MEF)2, were also enhanced in an IGF-1 signaling–dependent manner. The dynamic cytoskeletal localization of Csl and its dominant effects on cell shape and behavior and transcription factor activity suggest that Csl plays a role in the regulatory network through which muscle cells coordinate their structural and functional states during growth, adaptation, and repair.

We performed transesophageal echocardiography in 50 consecutive hospitalized patients with recent transient ischemic attack or stroke of embolic origin to determine whether transesophageal echocardiography is more sensitive than transthoracic echocardiography in detection of possible intracardiac sources of embolism. Twenty-six of 50 patients with a negative transthoracic echocardiogram for potential source of emboli had a transesophageal echocardiography study that demonstrated at least one intracardiac abnormality. Abnormalities noted by transesophageal echocardiography included five of 50 patients with either a left atrial or left atrial appendage clot, four patients with a patent foramen ovale, and nine patients with spontaneous echocardiographic contrast In 11 of 50 patients with no other source of embolism, we found highly mobile filamentous strands on the mitral valve, which have not been described previously. These mitral valve echo strands may represent a fissured surface or fibrosis that can serve as a nidus for thrombus formation. We detected no unexpected left ventricular thrombus or left atrial myxoma. Factors significantly associated with a greater likelihood of a positive transesophageal echocardiography study included left atrial enlargement, atrial fibrillation, and a calcified or thickened mitral valve. Our study suggests that transesophageal echocardiography is a valuable addition to transthoracic echocardiography in investigating potential intracardiac sources of embolism. (Stroke 1991^2:734-739)