Mitochondrial dysfunction is implicated in skeletal muscle atrophy and dysfunction with aging, with strong support for an increased mitochondrial‐mediated apoptosis in sedentary rodent models. ...Whether this applies to aged human muscle is unknown, nor is it clear whether these changes are caused by sedentary behavior. Thus, we examined mitochondrial function respiration, reactive oxygen species (ROS) emission, and calcium retention capacity (CRC) in permeabilized myofibers obtained from vastus lateralis muscle biopsies of healthy physically active young (23.7±2.7 yr; mean±sd) and older (71.2±4.9 yr) men. Although mitochondrial ROS and maximal respiratory capacity were unaffected, the acceptor control ratio was reduced by 18% with aging, suggesting mild uncoupling of oxidative phosphorylation. CRC was reduced by 50% with aging, indicating sensitization of the mitochondrial permeability transition pore (mPTP) to apoptosis. Consistent with the mPTP sensitization, older muscles showed a 3‐fold greater fraction of endonuclease G (a mitochondrial proapoptotic factor)‐positive myonuclei. Aged muscles also had lower mitophagic potential, based on a 43% reduction in Parkin to the voltage‐dependent anion channel (VDAC) protein ratio. Collectively, these results show that mitochondrial‐mediated apoptotic signaling is increased in older human muscle and suggest that accumulation of dysfunctional mitochondria with exaggerated apoptotic sensitivity is due to impaired mitophagy.—Gouspillou, G., Sgarioto, N., Kapchinsky, S., Purves‐Smith, F., Norris, B., Pion, C. H., Barbat‐Artigas, S., Lemieux, R, Taivassalo, T., Morais, J. A., Aubertin‐Leheudre, M., Hepple, R. T. Increased sensitivity to mitochondrial permeability transition and myonuclear translocation of endonuclease G in atrophied muscle of physically active older humans. FASEB J. 28, 28–1621 (1633). www.fasebj.org
The aim of this work was to conduct a systematic review of human studies on metabolite/lipid biomarkers of metabolic syndrome (MetS) and its components, and provide recommendations for future ...studies. The search was performed in MEDLINE, EMBASE, EMB Review, CINHAL Complete, PubMed, and on grey literature, for population studies identifying MetS biomarkers from metabolomics/lipidomics. Extracted data included population, design, number of subjects, sex/gender, clinical characteristics and main outcome. Data were collected regarding biological samples, analytical methods, and statistics. Metabolites were compiled by biochemical families including listings of their significant modulations. Finally, results from the different studies were compared. The search yielded 31 eligible studies (2005-2019). A first category of articles identified prevalent and incident MetS biomarkers using mainly targeted metabolomics. Even though the population characteristics were quite homogeneous, results were difficult to compare in terms of modulated metabolites because of the lack of methodological standardization. A second category, focusing on MetS components, allowed comparing more than 300 metabolites, mainly associated with the glycemic component. Finally, this review included also publications studying type 2 diabetes as a whole set of metabolic risks, raising the interest of reporting metabolomics/lipidomics signatures to reflect the metabolic phenotypic spectrum in systems approaches.
Autophagy is a critical process in the regulation of muscle mass, function and integrity. The molecular mechanisms regulating autophagy are complex and still partly understood. Here, we identify and ...characterize a novel FoxO-dependent gene, d230025d16rik which we named Mytho (Macroautophagy and YouTH Optimizer), as a regulator of autophagy and skeletal muscle integrity in vivo. Mytho is significantly up-regulated in various mouse models of skeletal muscle atrophy. Short term depletion of MYTHO in mice attenuates muscle atrophy caused by fasting, denervation, cancer cachexia and sepsis. While MYTHO overexpression is sufficient to trigger muscle atrophy, MYTHO knockdown results in a progressive increase in muscle mass associated with a sustained activation of the mTORC1 signaling pathway. Prolonged MYTHO knockdown is associated with severe myopathic features, including impaired autophagy, muscle weakness, myofiber degeneration, and extensive ultrastructural defects, such as accumulation of autophagic vacuoles and tubular aggregates. Inhibition of the mTORC1 signaling pathway in mice using rapamycin treatment attenuates the myopathic phenotype triggered by MYTHO knockdown. Skeletal muscles from human patients diagnosed with myotonic dystrophy type 1 (DM1) display reduced Mytho expression, activation of the mTORC1 signaling pathway and impaired autophagy, raising the possibility that low Mytho expression might contribute to the progression of the disease. We conclude that MYTHO is a key regulator of muscle autophagy and integrity.
Key points
Mitochondria are frequently implicated in the ageing of skeletal muscle, although the role of denervation in modulating mitochondrial function in ageing muscle is unknown.
We show that ...increased sensitivity to apoptosis initiation occurs prior to evidence of persistent denervation and is thus a primary mitochondrial defect in ageing muscle worthy of therapeutic targeting.
However, at more advanced age, mitochondrial function changes are markedly impacted by persistent sporadic myofibre denervation, suggesting the mitochondrion may be a less viable therapeutic target.
Experimental denervation modulates mitochondrial function, where changes in both reactive oxygen species (ROS) and sensitivity to permeability transition are implicated in the resultant muscle atrophy. Notably, although denervation occurs sporadically in ageing muscle, its impact on ageing muscle mitochondria is unknown. Because this information has important therapeutic implications concerning targeting the mitochondrion in ageing muscle, we examined mitochondrial function in skeletal muscle from four groups of humans, comprising two active (mean ± SD age: 23.7 ± 2.7 years and 71.2 ± 4.9 years) and two inactive groups (64.8 ± 3.1 years and 82.5 ± 4.8 years), and compared this with a murine model of sporadic denervation. We tested the hypothesis that, although some alterations of mitochondrial function in aged muscle are attributable to a primary organelle defect, mitochondrial dysfunction would be impacted by persistent denervation in advanced age. Both ageing in humans and sporadic denervation in mice increased mitochondrial sensitivity to permeability transition (humans, P = 0.004; mice, P = 0.01). To determine the contribution of sporadic denervation to mitochondrial function, we pharmacologically inhibited the denervation‐induced ROS response. This reduced ROS emission by 60% (P = 0.02) in sporadically denervated mouse muscle, which is similar to that seen in humans older than 75 years (–66%, P = 0.02) but not those younger than 75 years. We conclude that an increased sensitivity to permeability transition is a primary mitochondrial defect in ageing muscle. However, at more advanced age, when muscle atrophy becomes more clinically severe, mitochondrial function changes are markedly impacted by persistent sporadic denervation, making the mitochondrion a less viable therapeutic target.
Key points
Mitochondria are frequently implicated in the ageing of skeletal muscle, although the role of denervation in modulating mitochondrial function in ageing muscle is unknown.
We show that increased sensitivity to apoptosis initiation occurs prior to evidence of persistent denervation and is thus a primary mitochondrial defect in ageing muscle worthy of therapeutic targeting.
However, at more advanced age, mitochondrial function changes are markedly impacted by persistent sporadic myofibre denervation, suggesting the mitochondrion may be a less viable therapeutic target.
Summary Background Cachexia is a highly prevalent syndrome in cancer and chronic diseases. However, due to the heterogeneous features of cancer cachexia, its identification and classification ...challenge clinical practitioners. Objective To determine the clinical relevance of a cancer cachexia classification system in advanced cancer patients. Design Beginning with the four-stage classification system proposed for cachexia non-cachexia (NCa), pre-cachexia (PCa), cachexia (Ca) and refractory cachexia (RCa), we allocated patients in the cachexia stages according to five classification criteria available in clinical practice: 1) biochemistry (high C-reactive protein or leukocytes, or hypoalbuminemia, or anemia), 2) food intake (normal/decreased), weight loss: 3) moderate (≤5%) or 4) significant (>5%/past six months) and 5) performance status (Eastern Cooperative Oncology Group Performance Status ≥ 3). Thereafter, we determined if symptoms severity, body composition changes, functional levels, hospitalizations and survival rates varied significantly across patients according to the cachexia stages. Results Two-hundred and ninety-seven advanced cancer patients with primary gastrointestinal and lung tumors were included. Patients were classified into Ca (36%), PCa and RCa (21%, respectively) and NCa (15%). Significant ( p < 0.05) differences were observed among the cachexia stages for most of the outcomes (symptoms, body composition, handgrip strength, emergency room visits and length of hospital stays) according to the severity of cachexia. Survival analysis showed differences among all stages except between PCa and Ca. Conclusion The five criteria that we tested in this study can be used to identify the cachexia stages and predict important clinical, nutritional and functional outcomes. The lack of statistical difference between PCa and Ca in all the clinical outcomes examined may suggest either the PCa group include patients already affected by early cachexia or that more precise criteria need to be used to differentiate PCa vs. Ca patients. More studies are required to validate these findings.
Abstract
Background
The co-occurrence of slow walking speed and subjective cognitive complaint (SCC) in non-demented individuals defines motoric cognitive risk syndrome (MCR), which is a pre-dementia ...stage. There is no information on the association between MCR and incident dementia in Québec’s older population.
Objective
The study aims to examine the association of MCR and its individual components (i.e. SCC and slow walking speed) with incident dementia in community-dwelling older adults living in the province of Québec (Canada).
Design
Québec older people population-based observational cohort study with 3 years of follow-up.
Setting
Community dwellings.
Subjects
A subset of participants (n = 1,098) in ‘Nutrition as a determinant of successful aging: The Québec longitudinal study’ (NuAge).
Methods
At baseline, participants with MCR were identified. Incident dementia was measured at annual follow-up visits using the Modified Mini-Mental State (≤79/100) test and Instrumental Activity Daily Living scale (≤6/8) score values.
Results
The prevalence of MCR was 4.2% at baseline and the overall incidence of dementia was 3.6%. MCR (Hazard Ratio (HR) = 5.18, with 95% confidence interval (CI) = 2.43–11.03 and P ≤ 0.001) and SCC alone (HR = 2.54, with 95% CI = 1.33–4.85 and P = 0.005) were associated with incident dementia, but slow walking speed was not (HR = 0.81, with 95%CI = 0.25–2.63 and P = 0.736).
Conclusions
MCR and SCC are associated with incident dementia in NuAge study participants.
Ketone bodies may have anabolic effects in skeletal muscle via their capacity to stimulate protein synthesis. Whether orally ingested exogenous ketones can stimulate postprandial myofibrillar protein ...synthesis (MyoPS) rates with and without dietary protein co-ingestion is unknown.
This study aimed to evaluate the effects of ketone monoester intake and elevated blood β-hydroxybutyrate (β-OHB) concentration, with and without dietary protein co-ingestion, on postprandial MyoPS rates and mechanistic target of rapamycin complex 1 (mTORC1) pathway signaling.
In a randomized, double-blind, parallel group design, 36 recreationally active healthy young males (age: 24.2 ± 4.1 y; body fat: 20.9% ± 5.8%; body mass index: 23.4 ± 2 kg/m2) received a primed continuous infusion of L-ring-2H5-phenylalanine and ingested one of the following: 1) the ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KET), 2) 10 g whey protein (PRO), or 3) the combination of both (KET+PRO). Blood and muscle biopsy samples were collected during basal and postprandial (300 min) conditions to assess β-OHB, glucose, insulin, and amino acid concentrations, MyoPS rates, and mTORC1 pathway signaling.
Capillary blood β-OHB concentration increased similarly during postprandial conditions in KET and KET+PRO, with both being greater than PRO from 30 to 180 min (treatment × time interaction: P < 0.001). Postprandial plasma leucine and essential amino acid (EAA) incremental area under the curve (iAUC) over 300 min was greater (treatment: both P < 0.001) in KET+PRO compared with PRO and KET. KET, PRO, and KET+PRO stimulated postprandial MyoPS rates (0–300 min) higher than basal conditions absolute change: 0.020%/h; (95% CI: 0.013, 0.027%/h), 0.014%/h (95% CI: 0.009, 0.019%/h), 0.019%/h (95% CI: 0.014, 0.024%/h), respectively (time: P < 0.001), with no difference between treatments (treatment: P = 0.383) or treatment × time interaction (interaction: P = 0.245). mTORC1 pathway signaling responses did not differ between treatments (all P > 0.05).
Acute oral intake of a ketone monoester, 10 g whey protein, or their co-ingestion in the overnight postabsorptive state elicit a similar stimulation of postprandial MyoPS rates in healthy young males.
This trial was registered at clinicaltrials.gov as NCT04565444 (https://clinicaltrials.gov/study/NCT04565444).
Objective
The aim of this study was to determine the effect of age of obesity onset on senescence‐related markers in abdominal (AB) and femoral (FEM) subcutaneous adipose tissue (SAT) before and ...after moderate (~10%) weight loss.
Methods
AB and FEM SAT were collected from human females with childhood‐onset obesity (CO) or adult‐onset obesity (AO) before and after diet‐ and exercise‐induced weight loss. Immunofluorescence analysis of γH2AX/RAD51 (DNA damage/repair markers) and p53/p21 (senescence markers) was conducted in cultured preadipocytes, and senescence‐associated β‐galactosidase (SA‐β‐gal) activity was measured in SAT.
Results
CO had proportionately more AB and FEM preadipocytes with DNA damage (γH2AX+) and senescence markers (p53+ and/or p21+) than AO at baseline. The proportion of γH2AX+ FEM preadipocytes declined with weight loss in CO and was similar between groups after weight loss. The number of γH2AX foci in γH2AX+ preadipocytes decreased similarly between groups and regions with weight loss in parallel with an increase in RAD51. The proportion of p53+ and p21+ preadipocytes and SA‐β‐gal+ cells in SAT did not change with weight loss, but the total p21 intensity in p53+/p21+ FEM preadipocytes declined in AO.
Conclusions
These results provide preliminary evidence that females with CO have an accelerated preadipocyte aging state that improves with weight loss in terms of DNA damage but not senescence.
•Biomarkers of human immunosenescence are discussed.•Longitudinal studies are essential.•Associations of immune markers in older adults with clinical outcome are context-dependent.•There are no ...universal biomarkers of human immunosenescence.•There are common age-associated changes to peripheral immune markers in humans.
There is a great deal of debate on the question of whether or not we know what ageing is (Ref. Cohen et al., 2020). Here, we consider what we believe to be the especially confused and confusing case of the ageing of the human immune system, commonly referred to as “immunosenescence”. But what exactly is meant by this term? It has been used loosely in the literature, resulting in a certain degree of confusion as to its definition and implications. Here, we argue that only those differences in immune parameters between younger and older adults that are associated in some definitive manner with detrimental health outcomes and/or impaired survival prospects should be classed as indicators of immunosenescence in the strictest sense of the word, and that in humans we know remarkably little about their identity. Such biomarkers of immunosenescence may nonetheless indicate beneficial effects in other contexts, consistent with the notion of antagonistic pleiotropy. Identifying what could be true immunosenescence in this respect requires examining: (1) what appears to correlate with age, though generality across human populations is not yet confirmed; (2) what clearly is part of a suite of canonical changes in the immune system that happen with age; (3) which subset of those changes accelerates rather than slows aging; and (4) all changes, potentially population-specific, that accelerate agig. This remains an immense challenge. These questions acquire an added urgency in the current SARS-CoV-2 pandemic, given the clearly greater susceptibility of older adults to COVID-19.
Abstract
Denervation and mitochondrial impairment are implicated in age-related skeletal muscle atrophy and may play a role in physical frailty. We recently showed that denervation modulates muscle ...mitochondrial function in octogenarian men, but this has not been examined in elderly women. On this basis, we tested the hypothesis that denervation plays a modulating role in mitochondrial impairment in skeletal muscle from prefrail or frail elderly (FE) women. Mitochondrial respiratory capacity and reactive oxygen species emission were examined in permeabilized myofibers obtained from vastus lateralis muscle biopsies from FE and young inactive women. Muscle respiratory capacity was reduced in proportion to a reduction in a mitochondrial marker protein in FE, and mitochondrial reactive oxygen species emission was elevated in FE versus young inactive group. Consistent with a significant accumulation of neural cell adhesion molecule-positive muscle fibers in FE (indicative of denervation), a 50% reduction in reactive oxygen species production after pharmacologically inhibiting the denervation-mediated reactive oxygen species response in FE women suggests a significant modulation of mitochondrial function by denervation. In conclusion, our data support the hypothesis that denervation plays a modulating role in skeletal muscle mitochondrial function in FE women, suggesting therapeutic strategies in advanced age should focus on the causes and treatment of denervation.
PDF
