Physical performance level in sarcomeric mitochondria creatine kinase knockout mouse model throughout ageing

Abstract

Purpose: The objective of the present study was to establish the role of sarcomeric mitochondrial creatine kinase (Mt-CK) in muscle energy output during exercise in a murine model of ageing (the Mt-CK knock-out mouse, Mt-CK^-/-).

Methods: Three age groups of Mt-CK^-/- mice and control male mice (6, 9, and 18 months of age) underwent incremental treadmill running tests. The maximum speed (Vpeak) and maximal oxygen consumption (VO₂peak) values were recorded. Urine samples were analyzed using metabolomic techniques. The skeletal muscle (quadriceps) expression of proteins involved in mitochondria biogenesis, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and dynamin-related GTPase mitofusin 2 (Mnf2) were quantified.

Results: The VO₂ peak (normalized to heart weight: HW) of 18-month-old (mo) Mt-CK^-/- mice was 27% (p < 0.001) lower than in 18-mo control mice. The VO₂peak/HW ratio was 29% (p < 0.001) lower in 18-mo Mt-CK^-/- mice than in 6-mo (p < 0.001) and 32% (p < 0.001) than 9-mo Mt-CK^-/- mice. With a 0° slope, Vpeak was 10% (p < 0.05) lower in 18-mo Mt-CK^-/- mice than in 6-mo Mt-CK^-/- mice but did not differ when comparing the 18-mo and 6-mo control groups. The skeletal muscles weight normalized on body weight in 6-mo Mt-CK^-/- were 13 to 14% (p < 0.001, p < 0.05) lower versus the 6-mo control, in addition, the presence of branched-chain amino acids in the urine of 6-mo Mt-CK^-/- mice suggests an imbalance in protein turnover (catabolism rather than anabolism) but we did not observe any age-related differences. The expression of PGC-1α and Mnf2 proteins in the quadriceps showed that age-related effects were more prominent than genotype effects.

Conclusion: The present study showed ageing is potentialized by Mt-CK deficiency with regard to VO₂peak, Vpeak and mitochondrial protein expression. Our results support that Mt-CK^-/- mice undergo physiological adaptations, enabling them to survive and to perform as well as wild-type mice. Furthermore, it is possible that these adaptations in Mt-CK^-/- mice have a high energy cost and might trigger premature ageing.

Keywords: Ageing; Efficiency; Exercise performance; Mitochondrial creatine kinase; Skeletal muscle.