Abstract
ABSTRACTMitochondrial 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.
Highlights
Mitochondrial diseases are caused by genetic mutations in mitochondrial or nuclearDNA which affect the function of the mitochondrial respiratory chain thereby leading to a defective oxidative phosphorylation (Ishikawa and Nakada, 2020; Parikh et al, 2015; Thorburn, 2004)
Progressive body weight loss is associated with skeletal muscle atrophy without fatty replacement of muscle in Tfam KO mice
Skeletal muscle atrophy and replacement of skeletal muscle tissue by fat deposition or fibrotic tissue is a frequent feature in muscular disorders and has been reported in patients with mitochondrial myopathy, it is not a common feature (Olsen et al, 2003; Theodorou et al, 2012)
Summary
Mitochondrial diseases are caused by genetic mutations in mitochondrial or nuclear. DNA which affect the function of the mitochondrial respiratory chain thereby leading to a defective oxidative phosphorylation (Ishikawa and Nakada, 2020; Parikh et al, 2015; Thorburn, 2004). Skeletal muscles are commonly affected given that they require a high amount of energy and are highly dependent on oxidative phosphorylation for energy production. The mitochondrial transcription factor A (Tfam) encoded by nuclear DNA is a protein with a key role in mitochondrial DNA maintenance (Larsson et al, 1998). Disruption of Tfam has been shown to cause a global deficiency of all mitochondrial DNA-encoded proteins, affecting complexes I, III, IV, and V (Wredenberg et al, 2002)
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