SMN deficiency causes cardiac adrenergic insensitivity via activation of the cAMP-PKA pathway.

Spinal muscular atrophy (SMA) is a genetic disorder caused by reduced levels of the survival motor neuron (SMN) protein. The primary pathology involves the loss of motor neurons, however extra-neuronal tissues, including the heart, are also affected. The mechanisms underlying cardiac dysfunction in SMA are poorly understood, with some evidence suggesting impaired sympathetic innervation in vivo. To investigate the origins of cardiac dysfunction, we assessed the cardiac adrenergic response using an SMNΔ7 mouse model of SMA and cardiomyocytes derived from SMA patient induced pluripotent stem cells. The β adrenergic agonist, isoproterenol, failed to increase the amplitude of the Ca2+ transient or the heart rate. Adrenergic insensitivity was associated with a chronic activation of the cAMP-PKA signaling pathway downstream of the β adrenergic receptor. Basal cAMP levels and PKA activity were significantly elevated and PDE activity was reduced in SMN-deficient cardiac tissues. Collectively, these findings suggest a novel molecular mechanism for cardiac dysfunction in SMA that renders the heart insensitive to adrenergic stimulation and identifies the PDE pathway as a potential therapeutic target to ameliorate cardiac deficits in SMA.