Background: X-linked myotubular myopathy (XLMTM) is a severe neuromuscular disorder caused by pathogenic variants in MTM1 and characterized by profound muscle weakness, technological dependence, and early death. Progressive liver dysfunction is an emerging, potentially fatal consequence of the disease that is not well understood and directly impacts the response to transformative genetic therapies. While preclinical models replicate muscle pathology, they fail to display liver abnormalities. Patients with XLMTM also exhibit several nutrition related complication, including early-onset feeding difficulties requiring enteral nutrition. This study evaluated 1) whether XLMTM mouse models develop liver disease when challenged with patient-relevant dietary exposures, 2) how AAV-based therapies interact with this susceptibility, and 3) novel therapies to treat XLMTM liver disease. Methods: We studied global and hepatocyte-specific Mtm1 Ko mice under standard grain-based chow or purified dietary conditions starting at weaning with or without muscle-directed AAV-based gene replacement therapy. Clinical chemistry, liver histopathology, microbiome analyses and plasma metabolomic and liver transcriptomic analyses were performed. Non-viral lipid nanoparticle (LNP) delivery of MTM1 was evaluated as a rescue strategy. Results: Modified dietary exposure compared to chow revealed liver pathology in XLMTM mice consistent with those thus far reported in patients with XLMTM. Hepatocyte-specific Mtm1 deletion recapitulated key liver abnormalities, supporting a liver autonomous role of Mtm1. AAV therapy increased susceptibility to liver injury in XLMTM mice and induced hepatobiliary changes in wild-type mice. These changes were further associated with unique metabolomic and transcriptomic signatures, and shifts in fecal microbiota due to dietary exposures. Lastly, rescue of the XLMTM liver phenotype with LNP mRNA delivery was achieved in diet-sensitized mice, supporting a targeted strategy to treat XLMTM-associated liver injury. Conclusion: Our findings support a multi-hit model of XLMTM liver disease, reveal a previously underappreciated role of diet in modulating adverse effects of gene therapy, and identify a potential strategy to protect against severe liver injury in patients with XLMTM. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Pannia et al. (Fri,) studied this question.