Regulation of muscle and mitochondrial health by the mitochondrial fission protein Drp1 in aged mice

Dulac, Maude; Leduc‐Gaudet, Jean‐Philippe; Cefis, Marina; Ayoub, Marie-Belle; Reynaud, Olivier; Shams, Anwar; Moamer, Alaa; Ferreira, Marcos Francisco Nery; Hussain, Sabah N. A.; Gouspillou, Gilles

doi:10.1113/jp281752

Cited by 25 publications

(19 citation statements)

References 48 publications

(38 reference statements)

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“…33 For example, genetic ablation or overexpression of DRP1, the primary mediator of mitochondrial fission, impairs skeletal muscle integrity, induces muscle wasting, and diminishes metabolic control throughout the lifespan. 34,35 We found that BAM15 reduced mitochondrial fission in aged muscle indirectly by lowering expression of MiD49/51 and FIS1, the proteins responsible for DRP1 binding and docking on the outer mitochondrial membrane. 36 Importantly, restricting receptor/adaptor activity prevents excessive fission and generation of dysfunctional mitochondria while allowing routine fission to occur.…”

Section: Discussionmentioning

confidence: 81%

“…Mitochondria are dynamic organelles, whose morphology and function are regulated through continuous balancing of fission and fusion processes 33 . For example, genetic ablation or overexpression of DRP1, the primary mediator of mitochondrial fission, impairs skeletal muscle integrity, induces muscle wasting, and diminishes metabolic control throughout the lifespan 34,35 . We found that BAM15 reduced mitochondrial fission in aged muscle indirectly by lowering expression of MiD49/51 and FIS1, the proteins responsible for DRP1 binding and docking on the outer mitochondrial membrane 36 .…”

Section: Discussionmentioning

confidence: 86%

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Mitochondrial uncoupling attenuates sarcopenic obesity by enhancing skeletal muscle mitophagy and quality control

Dantas

Zunica

Heintz

et al. 2022

J cachexia sarcopenia muscle

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Background Sarcopenic obesity is a highly prevalent disease with poor survival and ineffective medical interventions. Mitochondrial dysfunction is purported to be central in the pathogenesis of sarcopenic obesity by impairing both organelle biogenesis and quality control. We have previously identified that a mitochondrial-targeted furazano [3,4-b]pyrazine named BAM15 is orally available and selectively lowers respiratory coupling efficiency and protects against diet-induced obesity in mice. Here, we tested the hypothesis that mitochondrial uncoupling simultaneously attenuates loss of muscle function and weight gain in a mouse model of sarcopenic obesity. Methods Eighty-week-old male C57BL/6J mice with obesity were randomized to 10 weeks of high fat diet (CTRL) or BAM15 (BAM15; 0.1% w/w in high fat diet) treatment. Body weight and food intake were measured weekly. Body composition, muscle function, energy expenditure, locomotor activity, and glucose tolerance were determined after treatment. Skeletal muscle was harvested and evaluated for histology, gene expression, protein signalling, and mitochondrial structure and function. Results BAM15 decreased body weight (54.0 ± 2.0 vs. 42.3 ± 1.3 g, P < 0.001) which was attributable to increased energy expenditure (10.1 ± 0.1 vs. 11.3 ± 0.4 kcal/day, P < 0.001). BAM15 increased muscle mass (52.7 ± 0.4 vs. 59.4 ± 1.0%, P < 0.001), strength (91.1 ± 1.3 vs. 124.9 ± 1.2 g, P < 0.0001), and locomotor activity (347.0 ± 14.4 vs. 432.7 ± 32.0 m, P < 0.001). Improvements in physical function were mediated in part by reductions in skeletal muscle inflammation (interleukin 6 and gp130, both P < 0.05), enhanced mitochondrial function, and improved endoplasmic reticulum homeostasis. Specifically, BAM15 activated mitochondrial quality control (PINK1-ubiquitin binding and LC3II, P < 0.01), increased mitochondrial activity (citrate synthase and complex II activity, all P < 0.05), restricted endoplasmic reticulum (ER) misfolding (decreased oligomer A11 insoluble/soluble ratio, P < 0.0001) while limiting ER stress (decreased PERK signalling, P < 0.0001), apoptotic signalling (decreased cytochrome C release and Caspase-3/9 activation, all P < 0.001), and muscle protein degradation (decreased 14-kDa actin fragment insoluble/soluble ratio, P < 0.001). Conclusions Mitochondrial uncoupling by agents such as BAM15 may mitigate age-related decline in muscle mass and function by molecular and cellular bioenergetic adaptations that confer protection against sarcopenic obesity.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 86%

Mitochondrial uncoupling attenuates sarcopenic obesity by enhancing skeletal muscle mitophagy and quality control

Dantas

Zunica

Heintz

et al. 2022

J cachexia sarcopenia muscle

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“…Aged mice demonstrate reduced DRP1 activity and alterations in mitochondrial morphology in several tissues, including skeletal muscle, neurons, and oocytes 75,76 . Interestingly, both muscle-specific DRP1 overexpression or DRP1 knockdown in 18-month-old mice causes muscle atrophy 77 . Recently, it has been shown that the RNA-binding protein pumilio 2 (PUM2) increases with age in worms, mice, and humans 67 .…”

Section: Box 1 | Epigenetic Modulations In Response To Mitochondrial ...mentioning

confidence: 99%

Pleiotropic effects of mitochondria in aging

et al. 2022

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itochondria are evolutionarily derived from alphaproteobacteria that evolved in symbiosis within eukaryotic cells 1 . Although most alphaproteobacterial genes were transferred to the eukaryotic nucleus, mitochondria retained their genome to translate the remaining protein-coding genes within their DNA. This requires complex coordination of the transcription and translation from two genomes, and the import and processing of proteins into the mitochondria in an ever-changing cellular milieu 2,3 . Disruption of these finely controlled processes has been shown to impair cellular homeostasis. To cope with this downside of endosymbiosis, mitochondria have evolved multiple stress-response pathways. The mitochondrial stress-response (MSR) network contributes to the reconstitution of cellular homeostasis by preventing mitochondrial proteotoxicity and by redistributing and removing irreversibly damaged elements of the mitochondria 4 . In recent years, we have gained considerable insights into why a decline in the robustness of these MSR pathways contributes to cellular damage and organismal deterioration. This is underlined by our emerging understanding of how different types of mitochondrial defects are co-regulated and interact across cellular and systemic processes.Here, we describe the pleiotropic effects of mitochondrial dysfunction in aging. We outline the major mitochondrial stress pathways, how their failure is interconnected with the expansion of mitochondrial DNA mutations and deregulated metabolism, and how this affects cellular and organismal homeostasis. We furthermore provide an integrated map of how combined mitochondrial defects impact several features of aging, suggesting conserved links that could potentially be harnessed to slow the aging process. We refer readers to other comprehensive reviews on topics not covered in depth here, such as cellular senescence, stem cell function, and reactive oxygen species (ROS) [5][6][7] .

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“…Our previous work suggests that loss of SIRT1, an important regulator of mitochondrial biogenesis via activation of protein peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC1α) 15 in MSCs, reduces the restoration of muscle function after an injury. 16 Further, reducing mitochondrial biogenesis and Drp1 expression increases fibrosis, 17,18 while reducing mitochondria-induced ROS accumulation can lower muscle fibrosis. 19 Because reducing PGC1α-regulated mitochondrial biogenesis can inhibit muscle repair, we hypothesized that increasing functional mitochondria in injured muscle would reduce muscle fibrosis and improve restoration of muscle function.…”

Section: Introductionmentioning

confidence: 99%

Mitochondria transplant therapy improves regeneration and restoration of injured skeletal muscle

Paez

Pitzer

Ferrandi

et al. 2023

J cachexia sarcopenia muscle

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Background Injection of exogenous mitochondria has been shown to improve the ischaemia‐damaged myocardium, but the effect of mitochondrial transplant therapy (MTT) to restore skeletal muscle mass and function has not been tested following neuromuscular injury. Therefore, we tested the hypothesis that MTT would improve the restoration of muscle function after injury. Methods BaCl2 was injected into the gastrocnemius muscle of one limb of 8–12‐week‐old C57BL/6 mice to induce damage without injury to the resident stem cells. The contralateral gastrocnemius muscle was injected with phosphate‐buffered saline (PBS) and served as the non‐injured intra‐animal control. Mitochondria were isolated from donor mice. Donor mitochondria were suspended in PBS or PBS without mitochondria (sham treatment) and injected into the tail vein of BaCl2 injured mice 24 h after the initial injury. Muscle repair was examined 7, 14 and 21 days after injury. Results MTT did not increase systemic inflammation in mice. Muscle mass 7 days following injury was 21.9 ± 2.1% and 17.4 ± 1.9% lower (P < 0.05) in injured as compared with non‐injured intra‐animal control muscles in phosphate‐buffered saline (PBS)‐ and MTT‐treated animals, respectively. Maximal plantar flexor muscle force was significantly lower in injured as compared with uninjured muscles of PBS‐treated (−43.4 ± 4.2%, P < 0.05) and MTT‐treated mice (−47.7 ± 7.3%, P < 0.05), but the reduction in force was not different between the experimental groups. The percentage of collagen and other non‐contractile tissue in histological muscle cross sections, was significantly greater in injured muscles of PBS‐treated mice (33.2 ± 0.2%) compared with MTT‐treated mice (26.5 ± 0.2%) 7 days after injury. Muscle wet weight and maximal muscle force from injured MTT‐treated mice had recovered to control levels by 14 days after the injury. However, muscle mass and force had not improved in PBS‐treated animals by 14 days after injury. The non‐contractile composition of the gastrocnemius muscle tissue cross sections was not different between control, repaired PBS‐treated and repaired MTT‐treated mice 14 days after injury. By 21 days following injury, PBS‐treated mice had fully restored gastrocnemius muscle mass of the injured muscle to that of the uninjured muscle, although maximal plantar flexion force was still 19.4 ± 3.7% (P < 0.05) lower in injured/repaired gastrocnemius as compared with uninjured intra‐animal control muscles. Conclusions Our results suggest that systemic mitochondria delivery can enhance the rate of muscle regeneration and restoration of muscle function following injury.

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Regulation of muscle and mitochondrial health by the mitochondrial fission protein Drp1 in aged mice

Abstract: support-information-section).

Cited by 25 publications

References 48 publications

Mitochondrial uncoupling attenuates sarcopenic obesity by enhancing skeletal muscle mitophagy and quality control

Mitochondrial uncoupling attenuates sarcopenic obesity by enhancing skeletal muscle mitophagy and quality control

Pleiotropic effects of mitochondria in aging

Mitochondria transplant therapy improves regeneration and restoration of injured skeletal muscle

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