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

R Niel; L Le Moyec; T Launay; L Mille-Hamard; M N Triba; O Maciejak; V L Billat; I Momken

doi:10.1016/j.exger.2021.111246

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

Exp Gerontol. 2021 Apr:146:111246. doi: 10.1016/j.exger.2021.111246. Epub 2021 Jan 27.

Authors

R Niel¹, L Le Moyec², T Launay³, L Mille-Hamard¹, M N Triba⁴, O Maciejak⁵, V L Billat¹, I Momken⁶

Affiliations

¹ Université Paris-Saclay, Université d'Evry, 23 Boulevard François Mitterrand, 91000 Évry-Courcouronnes, France.
² Université Paris-Saclay, Université d'Evry, 23 Boulevard François Mitterrand, 91000 Évry-Courcouronnes, France; Unité Molécules de Communication et Adaptation des Micro-organismes (MCAM), UMR7245 CNRS/Muséum National d'Histoire Naturelle, 63, rue Buffon CP54, 75005 Paris, France.
³ Université de Paris, Animal Genetic and Integrative Biology, INRAE, University of Paris-Saclay, AgroParisTech, 78350 Jouy-en-Josas, France.
⁴ Université Paris 13, Sorbonne Paris Cité, Laboratoire Chimie, Structures, Propriétés de Biomatériaux et d'Agents Thérapeutiques (CSPBAT), Unité Mixte de Recherche (UMR) 7244, Centre National de Recherche Scientifique (CNRS), France.
⁵ Unité d'Analyse et Modélisation pour la Biologie et l'Environnement (LAMBE), Université Paris-Saclay, Univ Evry, Evry, France.
⁶ Université Paris-Saclay, Université d'Evry, 23 Boulevard François Mitterrand, 91000 Évry-Courcouronnes, France; Université Paris-Saclay, Faculté de Pharmacie, Inserm, UMR-S 1180, Châtenay-Malabry, France. Electronic address: Iman.momken@universite-paris-saclay.fr.

PMID: 33515657
DOI: 10.1016/j.exger.2021.111246

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aging / genetics
Animals
Creatine Kinase* / metabolism
Male
Mice
Mice, Knockout
Mitochondria / metabolism
Mitochondria, Muscle / metabolism
Muscle, Skeletal / metabolism
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
Physical Conditioning, Animal*
Physical Functional Performance
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Transcription Factors
Creatine Kinase