Impaired aerobic capacity and premature fatigue preceding muscle weakness in the skeletal muscle Tfam-knockout mouse model
Mitochondrial diseases are genetic disorders that lead to impaired mitochondrial function, resulting in exercise intolerance and muscle weakness. In patients, muscle fatigue due to defects in mitochondrial oxidative capacities commonly precedes muscle weakness. In mice, deletion of the fast-twitch s...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
The Company of Biologists
2021-09-01
|
| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/14/9/dmm048981 |
| _version_ | 1818337408963313664 |
|---|---|
| author | Benjamin Chatel Sylvie Ducreux Zeina Harhous Nadia Bendridi Isabelle Varlet Augustin C. Ogier Monique Bernard Julien Gondin Jennifer Rieusset Håkan Westerblad David Bendahan Charlotte Gineste |
| author_facet | Benjamin Chatel Sylvie Ducreux Zeina Harhous Nadia Bendridi Isabelle Varlet Augustin C. Ogier Monique Bernard Julien Gondin Jennifer Rieusset Håkan Westerblad David Bendahan Charlotte Gineste |
| author_sort | Benjamin Chatel |
| collection | DOAJ |
| description | Mitochondrial diseases are genetic disorders that lead to impaired mitochondrial function, resulting in exercise intolerance and muscle weakness. In patients, muscle fatigue due to defects in mitochondrial oxidative capacities commonly precedes muscle weakness. In mice, deletion of the fast-twitch skeletal muscle-specific Tfam gene (Tfam KO) leads to a deficit in respiratory chain activity, severe muscle weakness and early death. Here, we performed a time-course study of mitochondrial and muscular dysfunctions in 11- and 14-week-old Tfam KO mice, i.e. before and when mice are about to enter the terminal stage, respectively. Although force in the unfatigued state was reduced in Tfam KO mice compared to control littermates (wild type) only at 14 weeks, during repeated submaximal contractions fatigue was faster at both ages. During fatiguing stimulation, total phosphocreatine breakdown was larger in Tfam KO muscle than in wild-type muscle at both ages, whereas phosphocreatine consumption was faster only at 14 weeks. In conclusion, the Tfam KO mouse model represents a reliable model of lethal mitochondrial myopathy in which impaired mitochondrial energy production and premature fatigue occur before muscle weakness and early death. |
| first_indexed | 2024-12-13T14:54:45Z |
| format | Article |
| id | doaj.art-1d6c38b12e5640108ab99eb5d7016953 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-12-13T14:54:45Z |
| publishDate | 2021-09-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-1d6c38b12e5640108ab99eb5d70169532022-12-21T23:41:16ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112021-09-0114910.1242/dmm.048981048981Impaired aerobic capacity and premature fatigue preceding muscle weakness in the skeletal muscle Tfam-knockout mouse modelBenjamin Chatel0Sylvie Ducreux1Zeina Harhous2Nadia Bendridi3Isabelle Varlet4Augustin C. Ogier5Monique Bernard6Julien Gondin7Jennifer Rieusset8Håkan Westerblad9David Bendahan10Charlotte Gineste11 Aix-Marseille Université, CRMBM UMR CNRS 7339, 13385 Marseille, France CarMeN Laboratory, UMR INSERM U1060/INRA U1397, Université Claude Bernard Lyon1, F-69310 Pierre-Bénite et F-69500 Bron, France CarMeN Laboratory, UMR INSERM U1060/INRA U1397, Université Claude Bernard Lyon1, F-69310 Pierre-Bénite et F-69500 Bron, France CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, 69600 Oullins, France Aix-Marseille Université, CRMBM UMR CNRS 7339, 13385 Marseille, France Aix-Marseille Université, Université de Toulon, CNRS, LIS, 13397 Marseille, France Aix-Marseille Université, CRMBM UMR CNRS 7339, 13385 Marseille, France Institut NeuroMyoGène, UMR CNRS 5310 - INSERM U1217, Université Claude Bernard Lyon 1, F-69008 Lyon, France CarMeN Laboratory, UMR INSERM U1060/INRA U1397, Université Claude Bernard Lyon1, F-69310 Pierre-Bénite et F-69500 Bron, France Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden Aix-Marseille Université, CRMBM UMR CNRS 7339, 13385 Marseille, France Aix-Marseille Université, CRMBM UMR CNRS 7339, 13385 Marseille, France Mitochondrial diseases are genetic disorders that lead to impaired mitochondrial function, resulting in exercise intolerance and muscle weakness. In patients, muscle fatigue due to defects in mitochondrial oxidative capacities commonly precedes muscle weakness. In mice, deletion of the fast-twitch skeletal muscle-specific Tfam gene (Tfam KO) leads to a deficit in respiratory chain activity, severe muscle weakness and early death. Here, we performed a time-course study of mitochondrial and muscular dysfunctions in 11- and 14-week-old Tfam KO mice, i.e. before and when mice are about to enter the terminal stage, respectively. Although force in the unfatigued state was reduced in Tfam KO mice compared to control littermates (wild type) only at 14 weeks, during repeated submaximal contractions fatigue was faster at both ages. During fatiguing stimulation, total phosphocreatine breakdown was larger in Tfam KO muscle than in wild-type muscle at both ages, whereas phosphocreatine consumption was faster only at 14 weeks. In conclusion, the Tfam KO mouse model represents a reliable model of lethal mitochondrial myopathy in which impaired mitochondrial energy production and premature fatigue occur before muscle weakness and early death.http://dmm.biologists.org/content/14/9/dmm048981mitochondrial myopathyenergy metabolismmuscle fatigueexercise intolerancemuscle weakness |
| spellingShingle | Benjamin Chatel Sylvie Ducreux Zeina Harhous Nadia Bendridi Isabelle Varlet Augustin C. Ogier Monique Bernard Julien Gondin Jennifer Rieusset Håkan Westerblad David Bendahan Charlotte Gineste Impaired aerobic capacity and premature fatigue preceding muscle weakness in the skeletal muscle Tfam-knockout mouse model Disease Models & Mechanisms mitochondrial myopathy energy metabolism muscle fatigue exercise intolerance muscle weakness |
| title | Impaired aerobic capacity and premature fatigue preceding muscle weakness in the skeletal muscle Tfam-knockout mouse model |
| title_full | Impaired aerobic capacity and premature fatigue preceding muscle weakness in the skeletal muscle Tfam-knockout mouse model |
| title_fullStr | Impaired aerobic capacity and premature fatigue preceding muscle weakness in the skeletal muscle Tfam-knockout mouse model |
| title_full_unstemmed | Impaired aerobic capacity and premature fatigue preceding muscle weakness in the skeletal muscle Tfam-knockout mouse model |
| title_short | Impaired aerobic capacity and premature fatigue preceding muscle weakness in the skeletal muscle Tfam-knockout mouse model |
| title_sort | impaired aerobic capacity and premature fatigue preceding muscle weakness in the skeletal muscle tfam knockout mouse model |
| topic | mitochondrial myopathy energy metabolism muscle fatigue exercise intolerance muscle weakness |
| url | http://dmm.biologists.org/content/14/9/dmm048981 |
| work_keys_str_mv | AT benjaminchatel impairedaerobiccapacityandprematurefatigueprecedingmuscleweaknessintheskeletalmuscletfamknockoutmousemodel AT sylvieducreux impairedaerobiccapacityandprematurefatigueprecedingmuscleweaknessintheskeletalmuscletfamknockoutmousemodel AT zeinaharhous impairedaerobiccapacityandprematurefatigueprecedingmuscleweaknessintheskeletalmuscletfamknockoutmousemodel AT nadiabendridi impairedaerobiccapacityandprematurefatigueprecedingmuscleweaknessintheskeletalmuscletfamknockoutmousemodel AT isabellevarlet impairedaerobiccapacityandprematurefatigueprecedingmuscleweaknessintheskeletalmuscletfamknockoutmousemodel AT augustincogier impairedaerobiccapacityandprematurefatigueprecedingmuscleweaknessintheskeletalmuscletfamknockoutmousemodel AT moniquebernard impairedaerobiccapacityandprematurefatigueprecedingmuscleweaknessintheskeletalmuscletfamknockoutmousemodel AT juliengondin impairedaerobiccapacityandprematurefatigueprecedingmuscleweaknessintheskeletalmuscletfamknockoutmousemodel AT jenniferrieusset impairedaerobiccapacityandprematurefatigueprecedingmuscleweaknessintheskeletalmuscletfamknockoutmousemodel AT hakanwesterblad impairedaerobiccapacityandprematurefatigueprecedingmuscleweaknessintheskeletalmuscletfamknockoutmousemodel AT davidbendahan impairedaerobiccapacityandprematurefatigueprecedingmuscleweaknessintheskeletalmuscletfamknockoutmousemodel AT charlottegineste impairedaerobiccapacityandprematurefatigueprecedingmuscleweaknessintheskeletalmuscletfamknockoutmousemodel |