Published paper: Creatine-deficiency models reveal distinct muscle effects

paper

Marker enzyme activities in hindleg from creatine-deficient AGAT and GAMT KO mice - differences between models, muscles, and sexes

Karina Barsunova, Marko Vendelin, Rikke Birkedal

Sci Rep, 2020 May 14; 10(1): 7956.

Significance

Creatine helps muscles rapidly meet changing energy demands. This published paper compared two mouse models of creatine deficiency caused by loss of AGAT or GAMT, enzymes required to make creatine. Loss of AGAT produced stronger muscle wasting and metabolic changes, particularly in fast, glycolytic muscles, whereas loss of GAMT had milder effects. The findings show that creatine-deficiency models are not interchangeable and that both muscle type and sex can affect how deficiency changes muscle metabolism.

Abstract

Creatine kinase (CK) functions as an energy buffer in muscles. Its substrate, creatine, is generated by L-arginine:glycine amidinotransferase (AGAT) and guanidinoacetate N-methyltransferase (GAMT). Creatine deficiency has more severe consequences for AGAT than GAMT KO mice. In the present study, to characterize their muscle phenotype further, we recorded the weight of tibialis anterior (TA), extensor digitorum longus (EDL), gastrocnemius (GAS), plantaris (PLA) and soleus (SOL) from creatine-deficient AGAT and GAMT, KO and WT mice. In GAS, PLA and SOL representing glycolytic, intermediate and oxidative muscle, respectively, we recorded the activities of pyruvate kinase (PK), lactate dehydrogenase (LDH), citrate synthase (CS) and cytochrome oxidase (CO). In AGAT KO compared to WT mice, muscle atrophy and differences in marker enzyme activities were more pronounced in glycolytic than oxidative muscle. In GAMT KO compared to WT, the atrophy was modest, differences in PK and LDH activities were minor, and CS and CO activities were slightly higher in all muscles. SOL from males had higher CS and CO activities compared to females. Our results add detail to the characterization of AGAT and GAMT KO skeletal muscle phenotypes and illustrate the importance of taking into account differences between muscles, and differences between sexes.