Crippa et al. identify a family of microRNAs that stop cardiac progenitors from abnormally differentiating into skeletal muscle, a function that may be disrupted in some types of human muscular dystrophies.
Some pericytes—the cells that wrap around the outside of blood vessels—have the ability to differentiate into cardiac or skeletal muscle, depending on the tissue in which they are located. Crippa et al. isolated these progenitors from the hearts of mice lacking β-sarcoglycan (Sgcb), a protein that maintains the integrity of both skeletal and cardiac muscle cells. Surprisingly, Sgcb-null cardiac progenitors differentiated into skeletal muscle myofibers in vitro, and the master regulator of skeletal myogenesis, MyoD, was abnormally expressed in the hearts of Sgcb-knockout animals.
The researchers found that the miRNA miR669a was strongly down-regulated in Sgcb-null cardiac progenitors because the leaky membranes of these cells let in calcium ions that activate calpain proteases, resulting in the degradation of a transcription factor required for miR669a production. In addition, a closely related miRNA, miR669q, was encoded within the Sgcb gene itself and was therefore completely absent from Sgcb-null progenitors. Both miRNAs were found to inhibit skeletal myogenesis by targeting MyoD directly.
Sgcb-null cardiac progenitors were unable to regenerate damaged heart tissue unless miR669 expression was restored to prevent their aberrant differentiation into skeletal myofibers. Conversely, cardiac progenitors lacking Sgcb and miR669 efficiently repaired damaged skeletal muscle. The authors now want to investigate whether mutations in human Sgcb, which cause limb-girdle muscular dystrophy type 2E, also perturb miRNA expression and cardiac progenitor differentiation.