Update Review about Metabolic Myopathies

Finsterer, Josef

doi:10.3390/life10040043

Cited by 12 publications

(17 citation statements)

References 90 publications

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“…In other words, muscles of Tfam KO mice showed an increased muscle fatigue before entering the state with progressive muscle atrophy and muscle weakness. These results extend those from previous studies showing a severe muscle weakness in more advanced stages of the disease (Gineste et al, 2015;Wredenberg et al, 2002) and support those reported in patients related to a progression from early premature fatigue to disabling muscle weakness already at rest (Finsterer, 2020;Tarnopolsky, 2016).…”

Section: Discussionsupporting

confidence: 91%

“…Premature muscle fatigue (i.e., faster decline in force during sustained or repeated contractions) is a typical feature in patients with mitochondrial myopathy (Finsterer, 2020;Tarnopolsky, 2016). We measured force production during 80 repeated submaximal contractions (1.5 s contractions given every 7.5 s).…”

Section: Faster Fatigue In Tfam Ko Than In Wt Mice At 11 and 14 Weeksmentioning

confidence: 99%

“…A similar lack of effect on muscle fatigue has been previously demonstrated in nemaline myopathy mouse models that also display a severe muscle weakness (Gineste et al, 2013;Gineste et al, 2020) and might then be due to the fact that experiments have been conducted in relatively late stages of the disease, i.e., when severe muscle weakness was established and the resulting energy consumption during contractions was decreased. Accordingly, premature fatigue (i.e., faster drop in force) related to decreased mitochondrial oxidative capacity has been shown to precede overt muscle weakness in mouse models with mitochondrial dysfunction as well as in patients with mitochondrial myopathies (Finsterer, 2020;Tarnopolsky, 2016;Yamada et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Impaired aerobic capacity and premature fatigue preceding muscle weakness in the skeletal muscle Tfam-knockout mouse model

Chatel

Ducreux

Harhous

et al. 2021

Disease Models &Amp; Mechanisms

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Mitochondrial diseases are genetic disorders leading to an impaired mitochondrial function and resulting in exercise intolerance and muscle weakness. In patients, muscle fatigue due to defects in mitochondrial oxidative capacities commonly precedes muscle weakness. In mice, the fast-twitch skeletal muscle-specific Tfam deletion (Tfam KO) leads to deficit in the 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 weeks Tfam KO mice, i.e., before and when mice are about to enter the terminal stage, respectively. While force in the unfatigued state was reduced in Tfam KO mice as compared to control littermates (WT) 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 WT 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 where impaired mitochondrial energy production and premature fatigue occur before muscle weakness and early death.

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Section: Discussionsupporting

confidence: 91%

Section: Faster Fatigue In Tfam Ko Than In Wt Mice At 11 and 14 Weeksmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Impaired aerobic capacity and premature fatigue preceding muscle weakness in the skeletal muscle Tfam-knockout mouse model

Chatel

Ducreux

Harhous

et al. 2021

Disease Models &Amp; Mechanisms

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show abstract

“…The copyright holder for this this version posted October 18, 2022. ; https://doi.org/10.1101/2022.10.14.511701 doi: bioRxiv preprint mitochondrial myopathies (16)(17)(18). Intriguingly, the CsA treatment-induced protection against muscle weakness, weight loss and early death in Tfam KO mice was not accompanied by any obvious signs of improved mitochondrial respiration, as judged from unaffected expression of proteins involved in mitochondrial energy metabolism (15).…”

Section: Introductionmentioning

confidence: 99%

Cyclosporin A delays the terminal disease stage inTfamKO mice without improving mitochondrial energy production

Chatel

Varlet

Ogier

et al. 2022

Preprint

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Mitochondrial myopathies are rare genetic disorders characterized by muscle weakness and exercise intolerance. Currently, no effective treatment exists for these myopathies. Interestingly, the pharmacological cyclophilin inhibitor cyclosporine A (CsA) extended lifespan and prevented loss of force and mitochondrial Ca2+ overload in muscle fibers in the skeletal muscle-specific Tfam knockout mouse model of lethal mitochondrial myopathy (Tfam KO). The unaffected expression of proteins involved in mitochondrial energy metabolism suggests that these improvements occurred without improvement in metabolism. In this study, we aimed at investigating the effects of four weeks of CsA administration on in vivo contractile function and mitochondrial energy production in Tfam KO mice. The treatment started before the terminal phase with severe muscle weakness and weight loss. Our results show that CsA treatment delayed progression into the terminal disease phase. This occurred without any obvious positive effects on mitochondrial energy production at rest or during fatigue induced by repeated contractions. In conclusion, cyclophilin inhibitors may have the potential of counteracting devastating muscle weakness in patients with mitochondrial myopathies most probably by preventing deleterious effects triggered by excessive mitochondrial Ca2+ uptake rather than by improving mitochondrial energy production.

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“…Avoiding strenuous exercise in fasted-states or during ongoing infections, along with dietary modifications (high carbohydrate and low fat) are the mainstays for management strategies [ 6 ]. Overall, current recommendations for metabolic myopathies advocate for supportive therapy and symptomatic management, ranging from routine cardiac monitoring to invasive ventilation [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Targeted Therapies for Metabolic Myopathies Related to Glycogen Storage and Lipid Metabolism: a Systematic Review and Steps Towards a ‘Treatabolome’

Manta

Spendiff

Lochmüller

et al. 2021

JND

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Background: Metabolic myopathies are a heterogenous group of muscle diseases typically characterized by exercise intolerance, myalgia and progressive muscle weakness. Effective treatments for some of these diseases are available, but while our understanding of the pathogenesis of metabolic myopathies related to glycogen storage, lipid metabolism and β-oxidation is well established, evidence linking treatments with the precise causative genetic defect is lacking. Objective: The objective of this study was to collate all published evidence on pharmacological therapies for the aforementioned metabolic myopathies and link this to the genetic mutation in a format amenable to databasing for further computational use in line with the principles of the “treatabolome” project. Methods: A systematic literature review was conducted to retrieve all levels of evidence examining the therapeutic efficacy of pharmacological treatments on metabolic myopathies related to glycogen storage and lipid metabolism. A key inclusion criterion was the availability of the genetic variant of the treated patients in order to link treatment outcome with the genetic defect. Results: Of the 1,085 articles initially identified, 268 full-text articles were assessed for eligibility, of which 87 were carried over into the final data extraction. The most studied metabolic myopathies were Pompe disease (45 articles), multiple acyl-CoA dehydrogenase deficiency related to mutations in the ETFDH gene (15 articles) and systemic primary carnitine deficiency (8 articles). The most studied therapeutic management strategies for these diseases were enzyme replacement therapy, riboflavin, and carnitine supplementation, respectively. Conclusions: This systematic review provides evidence for treatments of metabolic myopathies linked with the genetic defect in a computationally accessible format suitable for databasing in the treatabolome system, which will enable clinicians to acquire evidence on appropriate therapeutic options for their patient at the time of diagnosis.

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Update Review about Metabolic Myopathies

Cited by 12 publications

References 90 publications

Impaired aerobic capacity and premature fatigue preceding muscle weakness in the skeletal muscle Tfam-knockout mouse model

Impaired aerobic capacity and premature fatigue preceding muscle weakness in the skeletal muscle Tfam-knockout mouse model

Cyclosporin A delays the terminal disease stage inTfamKO mice without improving mitochondrial energy production

Targeted Therapies for Metabolic Myopathies Related to Glycogen Storage and Lipid Metabolism: a Systematic Review and Steps Towards a ‘Treatabolome’

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