#apaperaday: Urine titin as a novel biomarker for Duchenne muscular dystrophy

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Urine titin as a novel biomarker for Duchenne muscular dystrophy.

A paper by Ishii et al on using titin levels in urine as a biomarker for treatment response in the mdx mouse model. Published in the World Muscle Society journal of neuromuscular disorders. Doi 10.1016/j.nmd.2023.02.003

Duchenne is caused by lack of dystrophin which leads to progressive muscle wasting. Biomarkers that predict progression & treatment response are sought after. Yesterday we had a paper on serum markers in Becker patients. Blood sampling may seem a low invasive method to some, the average Duchenne patient however would disagree. Urine is an easier liquid to collect from a standpoint of invasiveness. Previous studies showed that in Duchenne patients urine titin peptides could be detected.

Titin is a gigantic protein in muscle (several times larger than dystrophin which is already large). With muscle turnover peptides of titin leak into the blood & are excreted in urine. Authors first show titin urine levels were higher in mdx mouse than wild types (all males).

When mdx mice were treated with a peptide conjugated exon skipping morpholino oligonucleotide (pPMO) (10 mg/kg) this induced >50% of dystrophin within 2 weeks in the gastrocnemius. That is really a lot – no results of the western blot are shown (authors used the WES system).

Treated mice showed a clear reduction in titin urine levels while the vehicle treated mice did not. Thus there was a clear treatment response. High numbers of mice were used (12 per group).

Finally authors tested titin levels in urine from Duchenne patients showing they are increased compared to healthy individuals and slightly decrease with age. No difference was found between ambulant and non ambulant patients

Authors discuss how this is the first time a treatment response is shown for urine titin in mice. However more work is needed which the authors clearly outline:

1. Here huge amounts of dystrophin are produced while in patients much lower levels are found so far. We need to know at which dystrophin levels titin in urine starts to decrease and whether this is linear with dystrophin level increases (dose response curves)
2. Correlations between titin urine levels & function need to be studied for Duchenne but (my addition) also Becker. So a good first step that of course needs more work. Note that others have already shown titin in urine of Duchenne patients and models, but not treatment response

Full disclosure: I consult for Takeda Pharma (producing this work) but was in no way involved in this publication. I commend the authors for their rigorous study. I do wonder how much dystrophin was expressed in other muscles and amazed at how much was restored after 1 injection.