Myotonic dystrophy (DM) is caused by a CTG expansion in the 3'-untranslated 
region of a protein kinase gene (DMPK). Cardiovascular disease is one of the 
most prevalent causes of death in DM patients. Electrophysiological studies in 
cardiac muscles from DM patients and from DMPK(-/-) mice suggested that DMPK is 
critical to the modulation of cardiac contractility and to the maintenance of 
proper cardiac conduction activity. However, there are no data regarding the 
molecular signaling pathways involved in DM heart failure. Here we show that 
DMPK expression in cardiac myocytes is highly enriched in the sarcoplasmic 
reticulum (SR) where it colocalizes with the ryanodine receptor and 
phospholamban (PLN), a muscle-specific SR Ca(2+)-ATPase (SERCA2a) inhibitor. 
Coimmunoprecipitation studies showed that DMPK and PLN can physically associate. 
Furthermore, purified wild-type DMPK, but not a kinase-deficient mutant (K110A 
DMPK), phosphorylates PLN in vitro. Subsequent studies using the DMPK(-/-) mice 
demonstrated that PLN is hypo-phosphorylated in SR vesicles from DMPK(-/-) mice 
compared with wild-type mice both in vitro and in vivo. Finally, we show that 
Ca(2+) uptake in SR is impaired in ventricular homogenates from DMPK(-/-) mice. 
Together, our data suggest the existence of a novel regulatory DMPK pathway for 
cardiac contractility and provide a molecular mechanism for DM heart pathology.