Creatine transporter (SLC6A8) knockout mice exhibit reduced muscle performance, disrupted mitochondrial Ca2+ homeostasis, and severe muscle atrophy
Abstract Creatine (Cr) is essential for cellular energy homeostasis, particularly in muscle and brain tissues. Creatine Transporter Deficiency (CTD), an X-linked disorder caused by mutations in the SLC6A8 gene, disrupts Cr transport, leading to intellectual disability, speech delay, autism, epilepsy...
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| Format: | Article |
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Nature Publishing Group
2025-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07381-x |
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| author | Irene Pertici Donato D’Angelo Denis Vecellio Reane Massimo Reconditi Ilaria Morotti Elena Putignano Debora Napoli Giorgia Rastelli Gaia Gherardi Agnese De Mario Rosario Rizzuto Simona Boncompagni Laura Baroncelli Marco Linari Marco Caremani Anna Raffaello |
| author_facet | Irene Pertici Donato D’Angelo Denis Vecellio Reane Massimo Reconditi Ilaria Morotti Elena Putignano Debora Napoli Giorgia Rastelli Gaia Gherardi Agnese De Mario Rosario Rizzuto Simona Boncompagni Laura Baroncelli Marco Linari Marco Caremani Anna Raffaello |
| author_sort | Irene Pertici |
| collection | DOAJ |
| description | Abstract Creatine (Cr) is essential for cellular energy homeostasis, particularly in muscle and brain tissues. Creatine Transporter Deficiency (CTD), an X-linked disorder caused by mutations in the SLC6A8 gene, disrupts Cr transport, leading to intellectual disability, speech delay, autism, epilepsy, and various non-neurological symptoms. In addition to neurological alterations, Creatine Transporter knockout (CrT−/y) mice exhibit severe muscle atrophy and functional impairments. This study provides the first characterization of the skeletal muscle phenotype in CrT−/y mice, revealing profound ultrastructural abnormalities accompanied by reduced fiber cross-sectional area and muscle performance. Notably, mitochondria are involved, as evidenced by disrupted cristae, increased mitochondrial size, impaired Ca2+ uptake, reduced membrane potential and ATP production. Mechanistically, the expression of atrophy-specific E3 ubiquitin ligases and suppression of the IGF1-Akt/PKB pathway, regulated by mitochondrial Ca2+ levels, further support the atrophic phenotype. These findings highlight the profound impact of Cr deficiency on skeletal muscle, emphasizing the need for targeted therapeutic strategies to address both the neurological and peripheral manifestations of CTD. Understanding the underlying mechanisms, particularly mitochondrial dysfunction, could lead to novel interventions for this disorder. |
| format | Article |
| id | doaj-art-faadfc1c76ca4973b49fe7f30b5b9002 |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-faadfc1c76ca4973b49fe7f30b5b90022025-08-20T02:48:16ZengNature Publishing GroupCell Death and Disease2041-48892025-02-0116111310.1038/s41419-025-07381-xCreatine transporter (SLC6A8) knockout mice exhibit reduced muscle performance, disrupted mitochondrial Ca2+ homeostasis, and severe muscle atrophyIrene Pertici0Donato D’Angelo1Denis Vecellio Reane2Massimo Reconditi3Ilaria Morotti4Elena Putignano5Debora Napoli6Giorgia Rastelli7Gaia Gherardi8Agnese De Mario9Rosario Rizzuto10Simona Boncompagni11Laura Baroncelli12Marco Linari13Marco Caremani14Anna Raffaello15PhysioLab (Department of Biology and Department of Experimental and Clinical Medicine), University of FlorenceDepartment of Biomedical Sciences, University of PadovaInstitute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum MunichPhysioLab (Department of Biology and Department of Experimental and Clinical Medicine), University of FlorencePhysioLab (Department of Biology and Department of Experimental and Clinical Medicine), University of FlorenceInstitute of Neuroscience, National Research Council (CNR)Institute of Neuroscience, National Research Council (CNR)Center for Advanced Studies and Technology, Department of Neuroscience, Imaging, and Clinical Sciences, University G. D’Annunzio of Chieti-PescaraDepartment of Biomedical Sciences, University of PadovaDepartment of Biomedical Sciences, University of PadovaDepartment of Biomedical Sciences, University of PadovaCenter for Advanced Studies and Technology, Department of Neuroscience, Imaging, and Clinical Sciences, University G. D’Annunzio of Chieti-PescaraInstitute of Neuroscience, National Research Council (CNR)PhysioLab (Department of Biology and Department of Experimental and Clinical Medicine), University of FlorencePhysioLab (Department of Biology and Department of Experimental and Clinical Medicine), University of FlorenceDepartment of Biomedical Sciences, University of PadovaAbstract Creatine (Cr) is essential for cellular energy homeostasis, particularly in muscle and brain tissues. Creatine Transporter Deficiency (CTD), an X-linked disorder caused by mutations in the SLC6A8 gene, disrupts Cr transport, leading to intellectual disability, speech delay, autism, epilepsy, and various non-neurological symptoms. In addition to neurological alterations, Creatine Transporter knockout (CrT−/y) mice exhibit severe muscle atrophy and functional impairments. This study provides the first characterization of the skeletal muscle phenotype in CrT−/y mice, revealing profound ultrastructural abnormalities accompanied by reduced fiber cross-sectional area and muscle performance. Notably, mitochondria are involved, as evidenced by disrupted cristae, increased mitochondrial size, impaired Ca2+ uptake, reduced membrane potential and ATP production. Mechanistically, the expression of atrophy-specific E3 ubiquitin ligases and suppression of the IGF1-Akt/PKB pathway, regulated by mitochondrial Ca2+ levels, further support the atrophic phenotype. These findings highlight the profound impact of Cr deficiency on skeletal muscle, emphasizing the need for targeted therapeutic strategies to address both the neurological and peripheral manifestations of CTD. Understanding the underlying mechanisms, particularly mitochondrial dysfunction, could lead to novel interventions for this disorder.https://doi.org/10.1038/s41419-025-07381-x |
| spellingShingle | Irene Pertici Donato D’Angelo Denis Vecellio Reane Massimo Reconditi Ilaria Morotti Elena Putignano Debora Napoli Giorgia Rastelli Gaia Gherardi Agnese De Mario Rosario Rizzuto Simona Boncompagni Laura Baroncelli Marco Linari Marco Caremani Anna Raffaello Creatine transporter (SLC6A8) knockout mice exhibit reduced muscle performance, disrupted mitochondrial Ca2+ homeostasis, and severe muscle atrophy Cell Death and Disease |
| title | Creatine transporter (SLC6A8) knockout mice exhibit reduced muscle performance, disrupted mitochondrial Ca2+ homeostasis, and severe muscle atrophy |
| title_full | Creatine transporter (SLC6A8) knockout mice exhibit reduced muscle performance, disrupted mitochondrial Ca2+ homeostasis, and severe muscle atrophy |
| title_fullStr | Creatine transporter (SLC6A8) knockout mice exhibit reduced muscle performance, disrupted mitochondrial Ca2+ homeostasis, and severe muscle atrophy |
| title_full_unstemmed | Creatine transporter (SLC6A8) knockout mice exhibit reduced muscle performance, disrupted mitochondrial Ca2+ homeostasis, and severe muscle atrophy |
| title_short | Creatine transporter (SLC6A8) knockout mice exhibit reduced muscle performance, disrupted mitochondrial Ca2+ homeostasis, and severe muscle atrophy |
| title_sort | creatine transporter slc6a8 knockout mice exhibit reduced muscle performance disrupted mitochondrial ca2 homeostasis and severe muscle atrophy |
| url | https://doi.org/10.1038/s41419-025-07381-x |
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