SENP7 deSUMOylase-governed transcriptional program coordinates sarcomere assembly and is targeted in muscle atrophy

Disorganization of the basic contractile unit of muscle cells, i.e., the sarcomeres, leads to suboptimal force generation and is a hallmark of muscle atrophy. Here, we demonstrate that the nuclear role of SENP7 deSUMOylase is pivotal for sarcomere organization. SENP7 expression is temporally upregulated in mature muscle cells and directly regulates transcription of the myosin heavy chain (MyHC-IId) gene. We identify SENP7-dependent deSUMOylation of flightless-1 (Fli-I) as a signal for Fli-I association with scaffold attachment factor b1 (Safb1). SENP7 deficiency leads to higher Fli-I SUMOylation and lower chromatin res-idency of Safb1, thus generating transcriptionally incompetent chromatin conformation on MyHC-IId. Conse-quently, lower expression of MyHC-IId causes sarcomere disorganization and disrupted muscle cell contrac-tion. Remarkably, cachexia signaling impedes the SENP7-governed transcriptional program, leading to muscle atrophy, with profound loss of motor protein MyHC-IId. We propose a SENP7-driven distinct tran-scription program as paramount for muscle cell function, which was found targeted in cachexia.