New Insights into SPEG Protein and Muscle Disease

Medical illustration of proteins

In a study published in the Journal of Cachexia, Sarcopenia and Muscle (JCSM), researchers at the University of Miami Miller School of Medicine, Boston Children’s Hospital, Brigham & Women’s Hospital and Harvard Medical School have shown how mutations in the SPEG protein can derail muscle function and cause disease.

Using a complex, multi-omic approach, the team showed how SPEG interacts with multiple skeletal and heart muscle proteins and regulates them.

“We have been studying SPEG for more than 10 years,” said Pankaj Agrawal, M.D., chief of the Division of Neonatology at the University of Miami Miller School of Medicine. “This is a critical protein for muscles and we are trying to understand how it works and find therapies.”

In the study, the team combined several sophisticated research techniques, including transcriptomics (measuring RNA levels), proteomics (measuring protein levels) and interactomics (identifying SPEG-interacting proteins). SPEG is a kinase protein. It delivers phosphate molecules to other proteins to alter their function, a process called phosphorylation. To understand these relationships, the researchers also utilized phosphoproteomics.

Miller School of Medicine pediatrician Dr. Pankaj Agrawal
Dr. Agrawal’s multi-omic investigations are revealing new insights into SPEG’s impact on muscle function.

“We found SPEG is phosphorylating some of the proteins associated with muscle contraction and are critical to that function,” said Dr. Agrawal. “It was a multi-omic approach to really understand this mechanism at the molecular level.”

These investigations showed that SPEG interacts with many proteins, including CMYA5, FSD2 and RyR1, which help form myospryn complexes that collectively make muscles contract.

Having dissected the SPEG pathway, Dr. Agrawal’s team will continue to investigate these proteins to better understand how they influence disease. The team is currently building a database of patients with SPEG mutations and have already been looking at cell and gene therapies that could modulate disease.

“We are going to look very hard at these proteins that interact with SPEG,” said Dr. Agrawal. “Previously, we identified a protein, called DNM2, which, when reduced in a disease model, can improve skeletal muscle function but not heart muscle. We see the patients and families who are suffering from these conditions, and it’s imperative that we do the difficult bench work to finally develop treatments.”

Tags: Division of Neonatology, Dr. Pankaj Agrawal, neonatology