PuSH - Publication Server of Helmholtz Zentrum München

Pertici, I.* ; D'Angelo, D.* ; Vecellio Reane, D. ; Reconditi, M.* ; Morotti, I.* ; Putignano, E.* ; Napoli, D.* ; Rastelli, G.* ; Gherardi, G.* ; De Mario, A.* ; Rizzuto, R.* ; Boncompagni, S.* ; Baroncelli, L.* ; Linari, M.* ; Caremani, M.* ; Raffaello, A.*

Creatine transporter (SLC6A8) knockout mice exhibit reduced muscle performance, disrupted mitochondrial Ca2+ homeostasis, and severe muscle atrophy.

Cell Death Dis. 16:99 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
Altmetric
Additional Metrics?
[➜Log in]
Edit extra informations Login
Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Skeletal-muscle; Deficiency; Kinase; Mouse; Respiration; Mutation; Tissues; Cloning; Sizes; Roles
ISSN (print) / ISBN 2041-4889
e-ISSN 2041-4889
Journal Cell Death & Disease
Quellenangaben Volume: 16, Issue: 1, Pages: , Article Number: 99 Supplement: ,
Publisher Nature Publishing Group
Publishing Place Campus, 4 Crinan St, London, N1 9xw, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)
Grants European Union funding program Horizon Europe
Italian Ministry of University and Research (MUR)
Next Generation
European Union - Next Generation EU
Italian Ministry of Health
Italian Ministry of Health - PRIN 20207P85MH