Metabolic (mal)adaptation of heart and skeletal muscle to frataxin depletion

Dr. Seifert’s lab has previously shown that in an animal model of FA (“UCLA” mice), heart function can be normal despite >98% loss of Frataxin (Fxn) and evidence of iron overload; normal function likely relies on preservation of fat oxidation and activation of processes that protect the heart. Interestingly, the hearts of Fxn-depleted mice show perturbations in 3 major signaling pathways, indicating that the Fxn-depleted heart is not normal. Some of these pathways may help to preserve heart function in the face of Fxn depletion, while others may lead to poor heart function if left unchecked. To understand how each pathway impacts the Fxn-depleted heart, the team will take advantage of existing small molecules: rapamycin (inhibits mTORC1 pathway), AICAR (activates AMPK pathway), and ISRIB (blocks the Integrated Stress Response pathway). The goal of this project is to test these small molecules in the UCLA mice, which have normal/compensated heart function, and in “MCK” mice that have complete Fxn loss in muscle soon after birth and show dramatic cardiac pathology. This group of investigators will determine if each of the 3 small molecules has a beneficial or harmful effect on heart function, size, and metabolism in both mouse models. They will also determine if these molecules can protect skeletal muscle in these animals from declining in mass and strength. This study will fundamentally address whether the observed changes in signaling pathways are beneficial or maladaptive and whether these pathways can be useful therapeutic targets.

Related Research Publications

PubMed | May 2022

Frataxin deficiency lowers lean mass and triggers the integrated stress response in skeletal muscle

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PubMed | Sep 2021

Adaptation of the heart to Frataxin depletion: Evidence that integrated stress response can predominate over mTORC1 activation

César Vásquez-Trincado, Monika Patel, Aishwarya Sivaramakrishnan, Carmen Bekeová, Lauren Anderson-Pullinger, Nadan Wang, Hsin-Yao Tang, Erin L Seifert