Function of PKD1 in Ang II-induced muscle wasting

Function of the stress-dependent kinase Protein Kinase D1 (Prkd1/PKD1) in angiotensin II (Ang II) induced muscle atrophy

Skeletal muscle wasting with accompanying cachexia is a life threatening complication in congestive heart failure. The molecular mechanisms are imperfectly understood, although an activated renin–angiotensin aldosterone system has been implicated. Angiotensin (Ang) II induces skeletal muscle atrophy in part by increased expression of muscle-enriched E3 ligase muscle RING-finger-1 (MuRF1/Trim63). In a recent study we elucidated the molecular mechanism of Ang II–induced skeletal muscle wasting. In a cDNA expression screen we identified the lysosomal hydrolase-coordinating transcription factor EB (TFEB) as novel regulator of the human MuRF1/Trim63 promoter. TFEB played a key role in regulating Ang II–induced skeletal muscle atrophy by transcriptional control of MuRF1/Trim63 via conserved E-box elements at its promoter. Inhibiting TFEB with small interfering RNA prevented Ang II–induced MuRF1/Trim63 expression and muscle atrophy. The histone deacetylase-5 (HDAC5), which was directly bound to and colocalized with TFEB, inhibited TFEB-induced MuRF1/Trim63 expression. The inhibition of TFEB by HDAC5 was reversed by PKD1, which was associated with HDAC5 and mediated its nuclear export. Mice lacking Prkd1/PKD1 in skeletal myocytes were resistant to Ang II–induced muscle wasting. In our study we proposed that elevated Ang II serum concentrations, as occur in patients with congestive heart failure, could activate the PKD1/HDAC5/TFEB/MuRF1 pathway to induce skeletal muscle wasting. Now we aim to elucidate further molecular mechanisms involved in this signalling pathway.

The Ang II/PKD1/HDAC5 signaling pathway regulates TFEB-induced MuRF1/Trim63 expression. The PKD1/HDAC5/TFEB/MuRF1 axis mediates Ang II induced skeletal muscle atrophy. Nuclear TFEB specifically binds to conserved E-box motifs in the MuRF1/Trim63 promoter localized close to its transcription start site. PKD1 together with HDAC5 controls TFEB activity at the MuRF1/Trim63 promoter. Inhibition of this signaling pathway could be important to combat Ang II associated muscle wasting disorders such as cardiac cachexia.