PuSH - Publication Server of Helmholtz Zentrum München: Creatine transporter (SLC6A8) knockout mice exhibit reduced muscle performance, disrupted mitochondrial Ca<sup>2+</sup> homeostasis, and severe muscle atrophy.

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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)

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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.

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PuSH - Publication Server of Helmholtz Zentrum München

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

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