MR spectroscopy of muscle and brain in guanidinoacetate methyltransferase (GAMT)‐deficient mice: Validation of an animal model to study creatine deficiency

Abstract

As a model for guanidinoacetate methyltransferase (GAMT) deficiency in humans, a gene knockout mouse model was generated. Here we report on several metabolic abnormalities in these mice, observed by in vivo and in vitro MR spectroscopy. In 1 H MR spectra of brain and hindleg muscle a clearly reduced signal of creatine (Cr) was observed in GAMT-deficient (GAMT-/-) animals. Analysis of the 1 H MR spectra of GAMT-/-brain indicated little or no increase of a signal for guanidinoacetate (Gua). In proton MR spectra of muscle, a broad signal of low intensity was observed for Gua. However, substantial Gua accumulation in intact muscle tissue was unequivocally confirmed in high-resolution magic angle spinning spectra, in which the Gua signal was resolved as one clear sharp singlet. In 31 P MR analysis of brain and hindleg muscle a strongly reduced phosphocreatine (PCr) content was shown. In addition, a signal of phosphorylated Gua at 0.5 ppm upfield of PCr was observed, with much higher intensity in muscle than in brain. This signal decreased when ischemia was applied to the muscle and recovered after ischemia was released. Overall, the in vivo 31 P and 1 H MR spectroscopy of GAMT-/-mice is similar to that of human GAMT deficiency. This opens up new avenues for the fundamental study of tissue-type dependence of creatine synthesis and transport and for diagnostic and therapeutic aspects of creatine deficiencies in humans. Magn Reson Med 50: 936 -943, 2003.

Quantitative Assessment of Metabolic Changes in the Developing Brain of C57BL/6 Mice by In Vivo Proton Magnetic Resonance Spectroscopy

“…This is in good accordance with observations in the thalamus region of children where the plateau was reached around the age of 3-4 years. Additionally, there is a good agreement between our results and those from in vivo MRS studies on brain metabolites in adult wild-type C57BL/6 mice [4,27].…”

Low‐field vs. high‐field proton MRS of mouse brain in vivo

“…Although not explicitly stated, Schwarcz et al (2) indeed used a set of 12 metabolite model spectra that included Tau. In line with a 7.0 T study (3), the analysis yielded Tau concentrations of 6.7 Ϯ 3.1, 6.9 Ϯ 1.6, and 6.0 Ϯ 2.3 mM for NMRI, BALB/c, and C57BL/6 mice, respectively. Their Cramer-Rao lower bounds (20 -35%) correspond with those for multiple metabolites reported by Tkáč et al (1).…”

Dynamic MRS and MRI of skeletal muscle function and biomechanics

“…Ca 2þ pumps), AK1 -/-and wild-type muscles exhibited similar rates of fatigue. Similar 31 P MRS studies have been done in muscle deficient in the enzyme guanidinoacetate methyltransferase (GAMT) (96,97), which is responsible for the synthesis of creatine. 31 P MR spectra of hindleg muscle of the GAMT -/-mice showed no PCr signal and instead showed the signal for phosphorylated guanidinoacetate (PGua), the immediate precursor of Cr, which is not normally present.…”