Creatine transporter–deficient rat model shows motor dysfunction, cerebellar alterations, and muscle creatine deficiency without muscle atrophy

Abstract

Creatine (Cr) is a nitrogenous organic acid and plays roles such as fast phosphate energy buffer to replenish ATP, osmolyte, antioxidant, neuromodulator, and as a compound with anabolic and ergogenic properties in muscle. Cr is taken from the diet or endogenously synthetized by the enzymes arginine:glycine amidinotransferase and guanidinoacetate methyltransferase, and specifically taken up by the transporter SLC6A8. Loss-of-function mutations in the genes encoding for the enzymes or the transporter cause creatine deficiency syndromes (CDS). CDS are characterized by brain Cr deficiency, intellectual disability with severe speech delay, behavioral troubles, epilepsy, and motor dysfunction. Among CDS, the X-linked Cr transporter deficiency (CTD) is the most prevalent with no efficient treatment so far. Different animal models of CTD show reduced brain Cr levels, cognitive deficiencies, and together they cover other traits similar to those of patients. However, motor function was poorly explored in CTD models, and some controversies in the phenotype exist in comparison with CTD patients. Our recently described Slc6a8 Y389C knock-in rat model of CTD showed mild impaired motor function, morphological alterations in cerebellum, reduced muscular mass, Cr deficiency, and increased guanidinoacetate content in muscle, although no consistent signs of muscle atrophy. Our results indicate that such motor dysfunction co-occurred with both nervous and muscle dysfunctions, suggesting that muscle strength and performance as well as neuronal connectivity might be affected by this Cr deficiency in muscle and brain.

Rescue of myocytes and locomotion through AAV2/9-2YF intracisternal gene therapy in a rat model of creatine transporter deficiency

“…However, only two of them show some of the motor dysfunction phenotypes of CTD. 26 , 34 In particular, our Slc6a8 Y389C rat shows mild impaired locomotor function with reduction of muscular mass and thinner myocytes. 33 , 34 …”

“… 26 , 34 In particular, our Slc6a8 Y389C rat shows mild impaired locomotor function with reduction of muscular mass and thinner myocytes. 33 , 34 …”

“… 15 We showed recently that our Slc6a8 Y389C rat CTD model presents mild impaired motor function as well as reduction of muscular mass and thinner myocytes. 33 , 34 We thus analyzed whether motor activity was improved in injected mKI. Motor function was evaluated with open-field (OF) and circular corridor (CC) tests, as well as by scoring of rearing (standing up on hind limbs, a spontaneous behavior requiring muscle performance, coordination, and stability for its execution; rearing “supported” if one or both superior limbs are used for support, or “unsupported” when no superior limb used).…”

Deep postnatal phenotyping of a new mouse model of nonketotic hyperglycinemia

“…For instance, only rat models and not mice of creatine transporter defect and of Lesh-Nyhan disease recapitulate the characteristic neurological symptoms, 77,78 and in galactosemia the rat, but not the mouse, shows liver dysfunction. 79 Because the mouse biochemistry reflects that in the human patients, the mouse model can be used to explore therapeutic strategies such as biochemical manipulations, gene therapeutic interventions, or even chaperone therapy given the reduced mutant protein.…”

Integrated bioinformatics, network pharmacology, and artificial intelligence to predict the mechanism of celastrol against muscle atrophy caused by colorectal cancer

“…Piezo1/KLF15/IL-6 axis-induced muscle atrophy ( Hirata et al, 2022 ) is an important regulatory pathway for muscle atrophy in mice ( Jagasia and Wagner, 2022 ). SLC6A8 knockdown results in a decrease in muscle mass ( Duran-Trio et al, 2022 ). KLF2 regulates skeletal muscle injury and regeneration ( Manoharan et al, 2019 ).…”