The accumulation of dysfunctional mitochondria has been implicated in aging, but a deeper understanding of mitochondrial dynamics and mitophagy during aging is missing. Here, we show that ...upregulating Drp1-a Dynamin-related protein that promotes mitochondrial fission-in midlife, prolongs Drosophila lifespan and healthspan. We find that short-term induction of Drp1, in midlife, is sufficient to improve organismal health and prolong lifespan, and observe a midlife shift toward a more elongated mitochondrial morphology, which is linked to the accumulation of dysfunctional mitochondria in aged flight muscle. Promoting Drp1-mediated mitochondrial fission, in midlife, facilitates mitophagy and improves both mitochondrial respiratory function and proteostasis in aged flies. Finally, we show that autophagy is required for the anti-aging effects of midlife Drp1-mediated mitochondrial fission. Our findings indicate that interventions that promote mitochondrial fission could delay the onset of pathology and mortality in mammals when applied in midlife.Mitochondrial fission and fusion are important mechanisms to maintain mitochondrial function. Here, the authors report that middle-aged flies have more elongated, or 'hyper-fused' mitochondria, and show that induction of mitochondrial fission in midlife, but not in early life, extends the health and life of flies.
In addition to skeletal muscle dysfunction, cancer cachexia is a systemic disease involving remodeling of nonmuscle organs such as adipose and liver. Impairment of mitochondrial function is ...associated with multiple chronic diseases. The tissue-specific control of mitochondrial function in cancer cachexia is not well defined. This study determined mitochondrial respiratory capacity and coupling control of skeletal muscle, white adipose tissue (WAT), and liver in colon-26 (C26) tumor-induced cachexia. Tissues were collected from PBS-injected weight-stable mice, C26 weight-stable mice and C26 mice with moderate (10% weight loss) and severe cachexia (20% weight loss). The respiratory control ratio (RCR) an index of oxidative phosphorylation (OXPHOS) coupling efficiency was low in WAT during the induction of cachexia because of high nonphosphorylating LEAK respiration. Liver RCR was low in C26 weight-stable and moderately cachexic mice because of reduced OXPHOS. Liver RCR was further reduced with severe cachexia, where Ant2 but not Ucp2 expression was increased. Ant2 was inversely correlated with RCR in the liver (
= -0.547,
< 0.01). Liver cardiolipin increased in moderate and severe cachexia, suggesting this early event may also contribute to mitochondrial uncoupling. Impaired skeletal muscle mitochondrial respiration occurred predominantly in severe cachexia, at complex I. These findings suggest that mitochondrial function is subject to tissue-specific control during cancer cachexia, whereby remodeling in WAT and liver arise early and may contribute to altered energy balance, followed by impaired skeletal muscle respiration. We highlight an under-recognized role of liver and WAT mitochondrial function in cancer cachexia and suggest mitochondrial function of multiple tissues to be therapeutic targets.
Background
While fish oil (FO) has attracted great attention due to their health-enhancing properties, its potential to enhance benefits from resistance exercise training (RET) has not been fully ...elucidated yet.
Aims
The aim of this study was to investigate effects of FO administration during 12 weeks of programmed RET on muscular strength, resting metabolic rate (RMR), and systemic inflammation in healthy older adults.
Methods
Twenty-eight healthy older adults were randomly assigned to three experimental groups: sedentary control (CON), resistance exercise training (RET), or RET combined with FO (RET-FO). A one-repetition (1RM) of maximum muscle strength, RMR, substrate oxidation, and blood inflammatory biomarkers were assessed before and after the intervention. Statistical significance was set at
p
≤ 0.05.
Results
1RM muscle strength was significantly increased in RET and RET-FO while substantially decreased in CON. RMR greatly increased in RET and RET-FO with no change in CON. RET-FO exhibited significantly increased fatty acid oxidation, but no change was found in CON and RET. Systemic interleukin 6 (IL-6) and C-reactive protein (CRP) were significantly decreased from baseline in RET-FO while no change was observed in CON and RET.
Conclusion
Our data indicate chronic RET reversed aging-induced loss of muscle strength and improved RMR, while FO administration combined with RET appears to enhance fat metabolism and mildly reduce some indicators of systemic inflammation.
Hepatic mitochondrial function loss is associated with cancer cachexia pathology in vivo. Here, we examined if hepatic mitochondrial defects observed in vivo in the cachexic liver also recapitulate ...during the in vitro treatment of mouse hepatocytes with tumor conditioned media. In vitro experiments were combined with proteome-wide expression analysis of cachexic liver tissue curated for mitochondrial dynamics and quality control proteins, to determine the fidelity of hepatic mitochondrial maladaptation in cancer cachexia pathology. AML12 hepatocytes were exposed to colon-26 (C26) and Lewis lung carcinoma (LLC) conditioned media for 6–72 h and assayed for cell viability, membrane potential, respiratory function, H
2
O
2
production, total ROS/RNS, and mitochondrial dynamics and quality control proteins by immunoblotting. Liver tissue from cachexic C26 mice was analyzed by TMT-based quantitative proteomics for in vivo comparison. Cell viability, membrane potential, H
2
O
2
production, total ROS/RNS, and respiration were decreased 48–72 h after exposure to C26 and/or LLC. Protein expression of treated hepatocytes and cachexic liver tissue showed altered mitochondrial dynamics and quality control, in a manner that suggests limited fusion and content mixing, but also impaired ability to fragment and clear damaged mitochondria. Two strategies to maintain mitochondrial health, therefore, may not be functioning sufficiently in the cachexic liver. Together these findings imply adverse effects of C26 and LLC exposure on hepatocyte health, due to impaired mitochondrial function and remodeling. Exposure of mouse hepatocytes to tumor conditioned media models aspects of cachexic liver mitochondria dysfunction in vivo and validates the importance of hepatic mitochondrial maladaptation in cancer cachexia pathology.
Mitochondrial stress and mitokines in aging Burtscher, Johannes; Soltany, Afsaneh; Visavadiya, Nishant P. ...
Aging cell,
February 2023, Letnik:
22, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Mitokines are signaling molecules that enable communication of local mitochondrial stress to other mitochondria in distant cells and tissues. Among those molecules are FGF21, GDF15 (both expressed in ...the nucleus) and several mitochondrial‐derived peptides, including humanin. Their responsiveness to mitochondrial stress induces mitokine‐signaling in response for example to exercise, following mitochondrial challenges in skeletal muscle. Such signaling is emerging as an important mediator of exercise‐derived and dietary strategy‐related molecular and systemic health benefits, including healthy aging. A compensatory increase in mitokine synthesis and secretion could preserve mitochondrial function and overall cellular vitality. Conversely, resistance against mitokine actions may also develop. Alterations of mitokine‐levels, and therefore of mitokine‐related inter‐tissue cross talk, are associated with general aging processes and could influence the development of age‐related chronic metabolic, cardiovascular and neurological diseases; whether these changes contribute to aging or represent “rescue factors” remains to be conclusively shown. The aim of the present review is to summarize the expanding knowledge on mitokines, the potential to modulate them by lifestyle and their involvement in aging and age‐related diseases. We highlight the importance of well‐balanced mitokine‐levels, the preventive and therapeutic properties of maintaining mitokine homeostasis and sensitivity of mitokine signaling but also the risks arising from the dysregulation of mitokines. While reduced mitokine levels may impair inter‐organ crosstalk, also excessive mitokine concentrations can have deleterious consequences and are associated with conditions such as cancer and heart failure. Preservation of healthy mitokine signaling levels can be achieved by regular exercise and is associated with an increased lifespan.
Mitokines signal mitochondrial stress to distant cells and tissues. Long‐lasting increases or decreases in mitokine levels are associated with diseases and age‐related functional decline. Controlled fluctuations of mitokines, such as in exercise, may improve mitokine sensitivity and promote healthy aging.
Tandem mass tag (TMT)‐based quantitative proteomics was used to examine protein expression in skeletal muscle from mice with moderate and severe cancer cachexia to study mechanisms underlying varied ...cachexia severity. Weight loss of 10% (moderate) and 20% (severe) was induced by injection of colon‐26 cancer cells in 10‐week old Balb/c mice. In moderate cachexia, enriched pathways reflected fibrin formation, integrin/mitogen‐activated protein kinase (MAPK) signaling, and innate immune system, suggesting an acute phase response and fibrosis. These pathways remained enriched in severe cachexia; however, energy‐yielding pathways housed in mitochondria were prominent additions to the severe state. These enrichments suggest distinct muscle proteome expression patterns that differentiate cachexia severity. When analyzed with two other mouse models, eight differentially expressed targets were shared including serine protease inhibitor A3N (Serpina3n), synaptophysin‐like protein 2 (Sypl2), Isocitrate dehydrogenase NAD subunit alpha, mitochondrial (Idh3a), peroxisomal acyl‐coenzyme A oxidase 1 (Acox1), collagen alpha‐1(VI) chain (Col6a1), myozenin 3 (Myoz3), UDP‐glucose pyrophosphorylase (Ugp2), and solute carrier family 41 member 3 (Slc41a3). Acox1 and Idh3a control lipid oxidation and NADH generation in the TCA cycle, respectively, and Col6a1 comprises part of type VI collagen with reported profibrotic functions, suggesting influential roles in cachexia. A potential target was identified in fragile X mental retardation syndrome‐related protein 1 (FXR1), an RNA‐binding protein not previously implicated in cancer cachexia. FXR1 decreased in cachexia and related linearly with weight change and myofiber size. These findings suggest distinct mechanisms associated with cachexia severity and potential biomarkers and therapeutic targets.
Prominent pathological features of Huntington's disease (HD) are aggregations of mutated Huntingtin protein (mHtt) in the brain and neurodegeneration, which causes characteristic motor (such as ...chorea and dystonia) and non-motor symptoms. However, the numerous systemic and peripheral deficits in HD have gained increasing attention recently, since those factors likely modulate disease progression, including brain pathology. While whole-body metabolic abnormalities and organ-specific pathologies in HD have been relatively well described, the potential mediators of compromised inter-organ communication in HD have been insufficiently characterized. Therefore, we applied an exploratory literature search to identify such mediators. Unsurprisingly, dysregulation of inflammatory factors, circulating mHtt, and many other messenger molecules (hormones, lipids, RNAs) were found that suggest impaired inter-organ communication, including of the gut-brain and muscle-brain axis. Based on these findings, we aimed to assess the risks and potentials of lifestyle interventions that are thought to improve communication across these axes: dietary strategies and exercise. We conclude that appropriate lifestyle interventions have great potential to reduce symptoms and potentially modify disease progression (possibly via improving inter-organ signaling) in HD. However, impaired systemic metabolism and peripheral symptoms warrant particular care in the design of dietary and exercise programs for people with HD.
Cachexia is a life-threatening complication of cancer traditionally characterized by weight loss and muscle dysfunction. Cachexia, however, is a systemic disease that also involves remodeling of ...nonmuscle organs. The liver exerts major control over systemic metabolism, yet its role in cancer cachexia is not well understood. To advance the understanding of how the liver contributes to cancer cachexia, we used quantitative proteomics and bioinformatics to identify hepatic pathways and cellular processes dysregulated in mice with moderate and severe colon-26 tumor-induced cachexia; ~300 differentially expressed proteins identified during the induction of moderate cachexia were also differentially regulated in the transition to severe cachexia. KEGG pathway enrichment revealed representation by oxidative phosphorylation, indicating altered hepatic mitochondrial function as a common feature across cachexia severity. Glycogen catabolism was also observed in cachexic livers along with decreased pyruvate dehydrogenase protein X component (Pdhx), increased lactate dehydrogenase A chain (Ldha), and increased lactate transporter Mct1. Together this suggests altered lactate metabolism and transport in cachexic livers, which may contribute to energetically inefficient interorgan lactate cycling. Acyl-CoA synthetase-1 (ACSL1), known for activating long-chain fatty acids, was decreased in moderate and severe cachexia based on LC-MS/MS analysis and immunoblotting. ACSL1 showed strong linear relationships with percent body weight change and muscle fiber size (R
= 0.73-0.76,
< 0.01). Mitochondrial coupling efficiency, which is compromised in cachexic livers to potentially increase energy expenditure and weight loss, also showed a linear relationship with ACSL1. Findings suggest altered mitochondrial and substrate metabolism of the liver in cancer cachexia, and possible hepatic targets for intervention.
The velocity and magnitude in which the eccentric phase of an exercise is completed directly affects performance during the concentric phase. Therefore, the purpose of this research was to ...investigate the effects of eccentric phase duration on concentric outcomes at 60% and 80% of one-repetition maximum (1RM) in the squat and bench press. Sixteen college-aged, resistance-trained males completed 1RM testing, established normative eccentric durations, and performed fast (0.75 times normative) and slow (2.0 times normative) metronome-controlled eccentric duration repetitions. Outcome measures assessed during the concentric phase were: average concentric velocity (ACV), peak concentric velocity (PCV), rating of perceived exertion (RPE), range of motion (ROM), and barbell path. Eccentric duration was significantly and inversely correlated with ACV at 60% (r = −0.408, p = 0.004) and 80% (r = −0.477, p = 0.001) of 1RM squat. At 60% of 1RM squat, both fast and slow eccentric conditions produced greater (p < 0.001) PCV than normative duration with fast also producing greater PCV than slow (p = 0.044). Eccentric duration had no impact on RPE, ROM, or barbell path. Our results report for the first time that resistance-trained males performing a deliberately faster eccentric phase may enhance their own squat and bench press performance.
Cachexia is a life-threatening complication of cancer that occurs in up to 80% of patients with advanced cancer. Cachexia reflects the systemic consequences of cancer and prominently features ...unintended weight loss and skeletal muscle wasting. Cachexia impairs cancer treatment tolerance, lowers quality of life, and contributes to cancer-related mortality. Effective treatments for cancer cachexia are lacking despite decades of research. High-throughput omics technologies are increasingly implemented in many fields including cancer cachexia to stimulate discovery of disease biology and inform therapy choice. In this paper, we present selected applications of omics technologies as tools to study skeletal muscle alterations in cancer cachexia. We discuss how comprehensive, omics-derived molecular profiles were used to discern muscle loss in cancer cachexia compared with other muscle-wasting conditions, to distinguish cancer cachexia from treatment-related muscle alterations, and to reveal severity-specific mechanisms during the progression of cancer cachexia from early toward severe disease.
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