Thyroid hormone (TH) actions and metabolism are intracellular events that require the transport of TH across the plasma membrane. This process is facilitated by TH transporters of which the monocarboxylate transporter 8 (MCT8) has been most intensively studied. Inactivating mutations in the X-linked MCT8 gene are associated with a severe form of mental retardation and neuromuscular abnormalities. Another characteristic feature of this disease (also known as Allan-Herndon-Dudley syndrome (AHDS)) are highly elevated circulating T3 concentrations that in turn can cause thyrotoxic symptoms such as hypermetabolism, fat and muscle wasting as well as tachycardia. In order to unravel the exact underlying pathogenic mechanisms, we generated Mct8 ko mice that also lack the T4-specific transporter Oatp1c1. These Mct8/Oatp1c1 double knock-out (dko) mice show elevated serum T3 levels as the patients and a hypothyoid state in the CNS due to an impaired TH transport into the brain. Mct8/Oatp1c1 deficient mice also display learning and memory deficits as well as pronounced locomotor deficiencies, thus replicating the patients´ phenotype. Here, we aim to elucidate the consequences of murine Mct8 and/or Oatp1c1 deficiency on skeletal muscle innervation, function and regeneration. Our preliminary studies of Mct8/Oatp1c1 dko mice point to a distinct role of both transporters during activation and/or differentiation of satellite cells, the stem cells of the muscle. We therefore want to dissect the exact cell-specific function of Mct8 and Oatp1c1 during muscle regeneration by exploiting conditional knock-out mice. Another aim of our project is to determine the impact of a single or combined Mct8/Oatp1c1 deficiency on the cardiovascular and metabolic system. For this purpose, we will determine heart rate, body temperature and energy expenditure of TH transporter deficient mice at different ambient temperatures and will dissect systemic from tissue-autonomous effects by performing ex vivo studies as well as pharmacological deinnervation. Current efforts to treat patients with MCT8 mutations aim to use the TH analog Triac (TA3) to bypass the defective cellular import and to restore TH signaling particularly in the brain. It is, however, unclear, to which extent this treatment affects neuromuscular, cardiovascular and metabolic functions. We there aim to investigate the skeletal muscle, cardiovascular and metabolic consequences of TA3 treatment in Mct8/Oatp1c1 dko mice and to elucidate beneficial as well as side-effects of the treatment. Overall, we expect that our proposed studies will provide novel information regarding the pathogenic mechanisms underlying AHDS that are of immediate clinical relevance.
|Effective start/end date||01.01.15 → 31.12.18|
In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):