Creatine serves as fast energy
buffer in organs of high-energy demand such as brain and skeletal muscle.
L-Arginine:glycine amidinotransferase (AGAT) and
guanidinoacetate N-methyltransferase are responsible for endogenous
creatine synthesis. Subsequent uptake into target organs like skeletal muscle, heart and brain is mediated by the
creatine transporter (CT1, SLC6A8).
Creatine deficiency syndromes are caused by defects of endogenous
creatine synthesis or transport and are mainly characterized by
intellectual disability, behavioral abnormalities, poorly developed muscle mass, and in some cases also
muscle weakness. CT1-deficiency is estimated to be among the most common causes of X-linked
intellectual disability and therefore the brain phenotype was the main focus of recent research. Unfortunately, very limited data concerning muscle
creatine levels and functions are available from patients with CT1 deficiency. Furthermore, different CT1-deficient mouse models yielded conflicting results and detailed analyses of their muscular phenotype are lacking. Here, we report the generation of a novel CT1-deficient mouse model and characterized the effects of
creatine depletion in skeletal muscle. HPLC-analysis showed strongly reduced total
creatine levels in skeletal muscle and heart. MR-spectroscopy revealed an almost complete absence of
phosphocreatine in skeletal muscle. Increased AGAT expression in skeletal muscle was not sufficient to compensate for insufficient
creatine transport. CT1-deficient mice displayed profound impairment of skeletal muscle function and morphology (i.e., reduced strength, reduced endurance, and
muscle atrophy). Furthermore, severely altered energy homeostasis was evident on magnetic resonance spectroscopy. Strongly reduced
phosphocreatine resulted in decreased
ATP/Pi levels despite an increased
inorganic phosphate to
ATP flux. Concerning
glucose metabolism, we show increased
glucose transporter type 4 expression in muscle and improved
glucose clearance in CT1-deficient mice. These metabolic changes were associated with activation of
AMP-activated protein kinase - a central regulator of energy homeostasis. In summary,
creatine transporter deficiency resulted in a severe
muscle weakness and
atrophy despite different compensatory mechanisms.