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.
