Deciphering the role of ADP-ribosylation in CardioLaminopathy

Protein ADP-ribosylation is a physiologically and pathologically important post-translational modification (PTM) that regulates numerous cellular activities. ADP-ribosylation quickly alters the cellular states under acute stress conditions and disease pathologies. Laminopathies are a group of disorders caused by mutations in the LMNA gene, which encodes A-type lamins, components of the nuclear lamina. Recent studies characterizing striated muscle laminopathies have provided novel perspectives on the role of the nuclear lamina and the pathological consequences of altered nuclear lamina. Interestingly, studies have revealed that nicotinamide adenine dinucleotide (NAD⁺) salvage pathway was altered in the cardiac tissues carrying LMNA mutations, which drastically reduced cellular NAD⁺ levels. It is interesting to speculate that these changes in NAD⁺ availability could induce global ADP-ribosylome changes in striated muscle laminopathies that affect cardiac function. To address this hypothesis, we defined the ADP-ribosylomes of heart tissues isolated from an autosomal-recessive Lmna^-H222P/H222P mouse model of Emery Dreifuss Muscular Dystrophy (EDMD), a striated muscle laminopathy, in which altered NAD⁺ homeostasis is thought to contribute cardiac dysfunction. Compilation of the individual WT and Lmna^-H222P/H222P ADP-ribosylomes using our well-established MS-based ADP-ribosylome revealed that the Lmna^-H222P/H222P mutation reduced ADP-ribosylation in mouse hearts. STRING analysis of the 291 ADP-ribosylated proteins identified in the WT mouse hearts revealed a specific enrichment in proteins required for mitochondrial and muscle contraction functions. Importantly, we also discovered that the Lmna^-H222P/H222P mutation specifically reduced the modification of mitochondrial, cell membrane, and secreted proteins. Collectively, these studies provide important steps forward for the rapidly developing field of ADP-ribosylation research and have provided novel mechanistic insights into the role of ADP-ribosylation in diverse biological samples under both healthy and disease conditions.