Transient receptor potential channel 6 regulates abnormal cardiac S-nitrosylation in Duchenne muscular dystrophy

Heaseung Sophia Chung, Grace Muller, Ronald J. Holewinski, Vidya Venkatraman, Guangshuo Zhu, Djahida Bedja, David A. Kass, Jennifer Van Eyk

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Duchenne muscular dystrophy (DMD) is an X-linked disorder with dystrophin loss that results in skeletal and cardiac muscle weakening and early death. Loss of the dystrophin–sarcoglycan complex delo-calizes nitric oxide synthase (NOS) to alter its signaling, and augments mechanosensitive intracellular Ca2+ influx. The latter has been coupled to hyperactivation of the nonselective cation channel, transient receptor potential canonical channel 6 (Trpc6), in isolated myocytes. As Ca2+ also activates NOS, we hypothesized that Trpc6 would help to mediate nitric oxide (NO) dysregulation and that this would be manifest in increased myocardial S-nitrosylation, a post-translational modification increasingly implicated in neurodegenerative, inflammatory, and muscle disease. Using a recently developed dual-labeling proteomic strategy, we identified 1,276 S-nitrosylated cysteine residues [S-nitrosothiol (SNO)] on 491 proteins in resting hearts from a mouse model of DMD (dmdmdx:utrn+/−). These largely consisted of mitochondrial proteins, metabolic regulators, and sarcomeric proteins, with 80% of them also modified in wild type (WT). S-nitrosylation levels, however, were increased in DMD. Genetic deletion of Trpc6 in this model (dmdmdx:utrn+/−:trpc6−/−) reversed ∼70% of these changes. Trpc6 deletion also ameliorated left ventricular dilation, improved cardiac function, and tended to reduce fibrosis. Furthermore, under catecholamine stimulation, which also increases NO synthesis and intracellular Ca2+ along with cardiac workload, the hypernitrosylated state remained as it did at baseline. However, the impact of Trpc6 deletion on the SNO proteome became less marked. These findings reveal a role for Trpc6-mediated hypernitrosylation in dmdmdx:utrn+/− mice and support accumulating evidence that implicates nitrosative stress in cardiac and muscle disease.

Original languageEnglish (US)
Pages (from-to)E10763-E10771
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number50
StatePublished - Dec 12 2017


  • Duchenne muscular dystrophy
  • Mass spectrometry
  • Nitric oxide synthase signaling
  • Protein S-nitrosylation
  • Trpc6

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Transient receptor potential channel 6 regulates abnormal cardiac S-nitrosylation in Duchenne muscular dystrophy'. Together they form a unique fingerprint.

Cite this