Psychobiological regulation of plasma and saliva GDF15 dynamics in health and mitochondrial diseases.

GDF15 (growth differentiation factor 15) is a marker of cellular energetic stress linked to physical-mental illness, aging, and mortality. However, questions remain about its dynamic properties and measurability in human biofluids other than blood. Here, we examine the natural dynamics and psychobiological regulation of plasma and saliva GDF15 in four human studies representing 4,749 samples from 188 individuals. We show that GDF15 protein is detectable in saliva (8% of plasma concentration), likely produced by salivary glands secretory duct cells. Plasma and saliva GDF15 levels are not correlated. Using a brief laboratory socio-evaluative stressor paradigm, we find that psychological stress increases plasma (+3.4-5.3%) and saliva GDF15 (+45%) with distinct kinetics, within minutes. Moreover, saliva GDF15 exhibits a robust awakening response, declining by ∼42-92% within 30-45 minutes from its peak level at the time of waking up. Clinically, individuals with genetic mitochondrial OxPhos diseases show elevated baseline plasma and saliva GDF15, and post-stress GDF15 levels in both biofluids correlate with multi-system disease severity, exercise intolerance, and the subjective experience of fatigue. Taken together, our data establish the dynamic properties of saliva GDF15, reveal it as a stress-sensitive, and as a clinically relevant marker of mitochondrial diseases. These findings point to a shared psychobiological pathway integrating metabolic and mental stress.

Navigating the Landscape of Translational Geroscience in Canada: A Comprehensive Evaluation of Current Progress and Future Directions.

The inaugural Canadian Conferences on Translational Geroscience were held as two complementary sessions in October and November 2023. The conferences explored the profound interplay between the biology of aging, social determinants of health, the potential societal impact of geroscience and the maintenance of health in aging individuals. Although topics such as cellular senescence, molecular and genetic determinants of aging and prevention of chronic disease were addressed, the conferences went on to emphasize practical applications for enhancing older people's quality of life. This manuscript summarizes the proceeding and underscores the synergy between clinical and fundamental studies. Future directions highlight national and global collaborations and the crucial integration of early-career investigators. This work charts a course for a national framework for continued innovation and advancement in translational geroscience in Canada.

MFN2 overexpression in skeletal muscles of young and old mice causes a mild hypertrophy without altering mitochondrial respiration and H2O2 emission.

AIM: Sarcopenia, the aging-related loss of muscle mass and function, is a debilitating process negatively impacting the quality of life of affected individuals. Although the mechanisms underlying sarcopenia are incompletely understood, impairments in mitochondrial dynamics, including mitochondrial fusion, have been proposed as a contributing factor. However, the potential of upregulating mitochondrial fusion proteins to alleviate the effects of aging on skeletal muscles remains unexplored. We therefore hypothesized that overexpressing Mitofusin 2 (MFN2) in skeletal muscle in vivo would mitigate the effects of aging on muscle mass and improve mitochondrial function. METHODS: MFN2 was overexpressed in young (7 mo) and old (24 mo) male mice for 4 months through intramuscular injections of an adeno-associated viruses. The impacts of MFN2 overexpression on muscle mass and fiber size (histology), mitochondrial respiration, and H2O2 emission (Oroboros fluororespirometry), and various signaling pathways (qPCR and western blotting) were investigated. RESULTS: MFN2 overexpression increased muscle mass and fiber size in both young and old mice. No sign of fibrosis, necrosis, or inflammation was found upon MFN2 overexpression, indicating that the hypertrophy triggered by MFN2 overexpression was not pathological. MFN2 overexpression even reduced the proportion of fibers with central nuclei in old muscles. Importantly, MFN2 overexpression had no impact on muscle mitochondrial respiration and H2O2 emission in both young and old mice. MFN2 overexpression attenuated the increase in markers of impaired autophagy in old muscles. CONCLUSION: MFN2 overexpression may be a viable approach to mitigate aging-related muscle atrophy and may have applications for other muscle disorders.

Acute ingestion of a ketone monoester, whey protein, or their co-ingestion in the overnight postabsorptive state elicit a similar stimulation of myofibrillar protein synthesis rates in young males: a double-blind randomized trial.

BACKGROUND: 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. OBJECTIVES: This study aimed to evaluate the effects of ketone monoester intake and elevated blood ß-hydroxybutyrate (ß-OHB) concentration, with and without dietary protein co-ingestion, on postprandial MyoPS rates and mechanistic target of rapamycin complex 1 (mTORC1) pathway signaling. METHODS: 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 ß-OHB, glucose, insulin, and amino acid concentrations, MyoPS rates, and mTORC1 pathway signaling. RESULTS: Capillary blood ß-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). CONCLUSIONS: 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).

Autophagy ablation in skeletal muscles worsens sepsis-induced muscle wasting, impairs whole-body metabolism, and decreases survival.

Septic patients frequently develop skeletal muscle wasting and weakness, resulting in severe clinical consequences and adverse outcomes. Sepsis triggers sustained induction of autophagy, a key cellular degradative pathway, in skeletal muscles. However, the impact of enhanced autophagy on sepsis-induced muscle dysfunction remains unclear. Using an inducible and muscle-specific Atg7 knockout mouse model (Atg7iSkM-KO), we investigated the functional importance of skeletal muscle autophagy in sepsis using the cecal ligation and puncture model. Atg7iSkM-KO mice exhibited a more severe phenotype in response to sepsis, marked by severe muscle wasting, hypoglycemia, higher ketone levels, and a decreased in survival as compared to mice with intact Atg7. Sepsis and Atg7 deletion resulted in the accumulation of mitochondrial dysfunction, although sepsis did not further worsen mitochondrial dysfunction in Atg7iSkM-KO mice. Overall, our study demonstrates that autophagy inactivation in skeletal muscles triggers significant worsening of sepsis-induced muscle and metabolic dysfunctions and negatively impacts survival.

PHAF1/MYTHO is a novel autophagy regulator that controls muscle integrity.

Skeletal muscles play key roles in movement, posture, thermogenesis, and whole-body metabolism. Autophagy plays essential roles in the regulation of muscle mass, function and integrity. However, the molecular machinery that regulates autophagy is still incompletely understood. In our recent study, we identified and characterized a novel Forkhead Box O (FoxO)-dependent gene, PHAF1/MYTHO (phagophore assembly factor 1/macro-autophagy and youth optimizer), as a novel autophagy regulator that controls muscle integrity. MYTHO/PHAF1 is upregulated in multiple conditions leading to muscle atrophy, and downregulation of its expression spares muscle atrophy triggered by fasting, denervation, cachexia and sepsis. Overexpression of PHAF1/MYTHO is sufficient to induce muscle atrophy. Prolonged downregulation of PHAF1/MYTHO causes a severe myopathic phenotype, which is characterized by impaired autophagy, muscle weakness, myofiber degeneration, mammalian target of rapamycin complex 1 (mTORC1) hyperactivation and extensive ultrastructural defects, such as accumulation of proteinaceous and membranous structures and tubular aggregates. This myopathic phenotype is attenuated upon administration of the mTORC1 inhibitor rapamycin. These findings position PHAF1/MYTHO as a novel regulator of skeletal muscle autophagy and tissue integrity.

Serum metabolomic adaptations following a 12-week high-intensity interval training combined to citrulline supplementation in obese older adults.

Physical activity and nutrition play important roles in preventing adverse health outcomes that accompany aging. It has been shown that high-intensity interval training (HIIT) combined with citrulline (CIT) supplementation can improve physical and functional capacities. The aim of this study was to evaluate serum metabolites following a 12-week HIIT combined or not with CIT in obese older adults, and to correlate the metabolic changes with clinico-biological parameters changes. Eighty-six obese older adults completed a 12-week HIIT program combined with a 10 g daily supplementation of either CIT or placebo (PLA) during a double-blinded randomized interventional trial. Only participants with blood samples at T0 (before the intervention) and/or T12 (after the intervention) were included in our sub-analysis (HIIT-PLA-T0: n = 44 and HIIT-PLA-T12: n = 28; HIIT-CIT-T0: n = 39 and HIIT-CIT-T12: n = 42). Serum samples were analyzed by different liquid or gas phase chromatography methods coupled to mass spectrometry. Among the identified metabolites, 44 changed significantly following the 12-week intervention (Time effect), and 10 of them were more affected when HIIT was combined with CIT (Time × Supp effect). Arginine increased significantly due to the 12-week intervention. Correlation analyses demonstrated that decreased triglyceride (TG) (16:1/18:1/16:0) and aspartic acid significantly correlated with a reduction of adiposity-related parameters (fat mass, leg lean mass, leptin, total triglycerides and low-density lipoprotein). Arginine, TG (16:1/18:1/16:0) and aspartic acid might constitute biomarkers of cardiometabolic health and adiposity. Further studies are needed to confirm these associations and understand the underlying mechanisms.Highlights A 12-week intervention involving high-intensity interval training (HIIT) with or without citrulline (CIT) supplementation induced adaptations in the serum metabolome of obese older adults through significant changes in 44 metabolites.Changes in 23 metabolites were observed when a CIT supplementation was administered along with a 12-week HIIT intervention.TG (16:1/18:1/16:0) correlated with several adiposity parameters including leptin, triglycerides, legs lean mass.Aspartic acid correlated with several adiposity parameters including leptin, LDL cholesterol as well as android, arms and trunk fat mass.

MYTHO is a novel regulator of skeletal muscle autophagy and integrity.

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.

Serum Metabolome Adaptations Following 12 Weeks of High-Intensity Interval Training or Moderate-Intensity Continuous Training in Obese Older Adults.

Physical activity can be effective in preventing some of the adverse effects of aging on health. High-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) are beneficial interventions for the quality of life of obese older individuals. The understanding of all possible metabolic mechanisms underlying these beneficial changes has not yet been established. The aim of this study was to analyze changes in the serum metabolome after 12 weeks of HIIT and MICT in obese older adults. Thirty-eight participants performed either HIIT (n = 26) or MICT (n = 12) three times per week for 12 weeks. Serum metabolites as well as clinical and biological parameters were assessed before and after the 12-week intervention. Among the 364 metabolites and ratio of metabolites identified, 51 metabolites changed significantly following the 12-week intervention. Out of them, 21 significantly changed following HIIT intervention and 18 significantly changed following MICT. Associations with clinical and biological adaptations revealed that changes in acyl-alkyl-phosphatidylcholine (PCae) (22:1) correlated positively with changes in handgrip strength in the HIIT group (r = 0.52, p < 0.01). A negative correlation was also observed between 2-oxoglutaric acid and HOMA-IR (r = -0.44, p < 0.01) when considering both groups together (HIIT and MICT). This metabolite also correlated positively with quantitative insulin-sensitivity check index (QUICKI) in both groups together (r = 0.46, p < 0.01) and the HIIT group (r = 0.51, p < 0.01). Additionally, in the MICT group, fumaric acid was positively correlated with triglyceride levels (r = 0.73, p < 0.01) and acetylcarnitine correlated positively with low-density lipoprotein (LDL) cholesterol (r = 0.81, p < 0.01). These four metabolites might represent potential metabolites of interest concerning muscle strength, glycemic parameters, as well as lipid profile parameters, and hence, for a potential healthy aging. Future studies are needed to confirm the association between these metabolites and a healthy aging.

Wrist-worn devices for the measurement of heart rate and energy expenditure: A validation study for the Apple Watch 6, Polar Vantage V and Fitbit Sense.

The purpose of this study was to investigate the accuracy of 3 recently released wrist-worn devices (Apple Watch 6, Polar Vantage V and Fitbit Sense) for heart rate and energy expenditure during various activities. The study population consisted of 60 young healthy individuals (30 men and 30 women; age: 24.9 ± 3.0 years, BMI: 23.1 ± 2.7 kg/m2). Heart rate and energy expenditure were measured using the Polar H10 and Metamax 3B, respectively (reference measures) as well as with the 3 wrist-worn devices during 5 different activities (sitting, walking, running, resistance exercises and cycling). The Apple Watch 6 displayed the highest level of accuracy for heart rate measurement with a coefficient of variation (CV) (%) of less than 5% for all 5 activities, whereas the Polar Vantage V and the Fitbit Sense presented various degrees of accuracy (from high to poor accuracy) dependent on the activity (CVs between 2.44-8.80% and 4.14-10.76%, respectively). As for energy expenditure, all 3 devices displayed poor accuracy for all 5 physical activities (CVs between 14.68-24.85% for Apple Watch 6, 16.54-25.78% for Polar Vantage V and 13.44-29.66% for Fitbit Sense). Results of the present study indicate that the Apple Watch 6 was the most accurate for measuring heart rate across all 5 activities, whereas variable levels of accuracy for heart rate measurement for the Polar Vantage V and the Fitbit Sense were observed depending on the activity. As for energy expenditure, all 3 devices showed poor accuracy during all activities.Highlights The Apple Watch 6 was the most accurate for measuring heart rate, whereas the Polar Vantage V and Fitbit Sense showed variable results dependent on the activityThe Apple Watch 6, Polar Vantage V and Fitbit Sense showed poor accuracy for energy expenditure during 5 different physical activitiesHealthcare care professionals, athletes/coaches and the general population may want to proceed with caution on the clinical utility of energy expenditure of these devices during the implementation of an exercise training or nutritional programme.

The impact of high-fat feeding and parkin overexpression on skeletal muscle mass, mitochondrial respiration, and H2O2 emission.

Obesity is a major risk factor for developing various health problems, including insulin resistance and type 2 diabetes. Although controversial, accumulation of mitochondrial dysfunction, and notably an increase in mitochondrial reactive oxygen species (ROS) production, was proposed as a key contributor leading to obesity-induced insulin resistance. Here, our goal was to investigate whether Parkin overexpression, a key regulator of the removal of dysfunctional mitochondria through mitophagy, could confer protection against obesity-induced mitochondrial dysfunction. To this end, intramuscular injections of adeno-associated viruses (AAVs) were performed to overexpress Parkin in limb muscle of 6-mo-old mice fed a control diet (CD) or a high-fat diet (HFD) for 12 wk. An AAV-expressing the green fluorescent protein (GFP) was used as control. HFD increased fat mass, altered glycemia, and resulted in insulin resistance. Parkin overexpression resulted in an increase in muscle mass in both CD and HFD mice. In CD mice, Parkin overexpression increased maximal mitochondrial respiration and lowered H2O2 emission. HFD increased mitochondrial respiration and, surprisingly, also lowered H2O2 emission. Parkin overexpression did not significantly impact mitochondrial function in HFD mice. Taken altogether, our results indicate that Parkin overexpression positively impacts muscle and mitochondrial health under basal conditions and challenges the notion that intrinsic mitochondrial dysfunction is involved in the development of insulin resistance caused by high-fat feeding.

Dynamic behavior of cell-free mitochondrial DNA in human saliva.

Mitochondria contain their own genome that can be released in multiple biofluids such as blood and cerebrospinal fluid, as cell-free mitochondrial DNA (cf-mtDNA). In clinical studies, blood cf-mtDNA predicts mortality and higher cf-mtDNA levels are associated with mental and physical stress. However, the dynamics of cf-mtDNA has not been defined, and whether it can be measured non-invasively like other neuroendocrine markers in saliva has not been examined. Here we report cf-mtDNA in human saliva and establish its natural within-person dynamic behavior across multiple weeks. In a small proof-of-principle cohort of healthy adults, we first develop an approach to rapidly quantify salivary cf-mtDNA without DNA isolation, and demonstrate the existence of salivary cf-mtDNA. We then deploy this approach to perform an intensive repeated-measures analysis of two healthy men studied at 4 daily timepoints over 53-60 consecutive days (n = 212-220 observations each) with parallel measures of steroid hormones, self-reported daily mood, and health-related behaviors. Salivary cf-mtDNA exhibited a robust awakening response reaching up to two orders of magnitude 30-45 min after awakening, varied from day-to-day, and moderately correlated with the cortisol awakening response. In exploratory analyses, no consistent association with self-reported daily mood/health-related behaviors were found, although this requires further examination in future studies. Dynamic variation in cf-mtDNA was inversely related with salivary interleukin 6 (IL-6), inconsistent with a pro-inflammatory effect of salivary cf-mtDNA. The highly dynamic behavior of salivary cf-mtDNA opens the door to non-invasive studies examining the relevance of mtDNA signaling in relation to human health.

Clinical and Biological Adaptations in Obese Older Adults Following 12-Weeks of High-Intensity Interval Training or Moderate-Intensity Continuous Training.

Sarcopenia and obesity are considered a double health burden. Therefore, the implementation of effective strategies is needed to improve the quality of life of older obese individuals. The aim of this study was to compare the impact of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on functional capacities, muscle function, body composition and blood biomarkers in obese older adults. Adipose tissue gene expression and markers of muscle mitochondrial content and quality control involved in exercise adaptations were also investigated. Sixty-eight participants performed either HIIT (n = 34) on an elliptical trainer or MICT (n = 34) on a treadmill, three times per week for 12 weeks. HIIT produced significantly higher benefits on some physical parameters (six-minute walking test (HIIT: +12.4% vs. MICT: +5.2%); step test (HIIT: +17.02% vs. MICT: +5.9%); ten-repetition chair test (HIIT: -17.04% vs. MICT: -4.7%)). Although both HIIT and MICT led to an improvement in lower limb power (HIIT: +25.2% vs. MICT: +20.4%), only MICT led to higher improvement in lower limb muscle strength (HIIT: +4.3% vs. MICT: +23.2%). HIIT was more beneficial for increasing total lean body mass (HIIT: +1.58% vs. MICT: -0.81%), while MICT was more effective for decreasing relative gynoid fat mass (HIIT: -1.09% vs. MICT: -4.20%). Regarding adipose tissue gene expression, a significant change was observed for cell death-inducing DFFA (DNA fragmentation factor-alpha)-like effector A (CIDEA) in the HIIT group (A.U; HIIT at T0: 32.10 ± 39.37 vs. HIIT at T12: 48.2 ± 59.2). Mitochondrial transcription factor A (TFAM) content, a marker of mitochondrial biogenesis, increased significantly following HIIT (+36.2%) and MICT (+57.2%). A significant increase was observed in the HIIT group for Translocase of Outer Membrane 20 (TOM20; +54.1%; marker of mitochondrial content), Mitofusin-2 (MFN2; +71.6%; marker of mitochondrial fusion) and Parkin RBR E3 Ubiquitin Protein Ligase (PARKIN; +42.3%; marker of mitophagy). Overall, our results indicate that even though MICT (walking on treadmill) and HIIT (on an elliptical) are effective intervention strategies in obese older adults, HIIT appears to have slightly more beneficial effects. More specifically, HIIT led to higher improvements than MICT on functional capacities, lean mass and skeletal muscle markers of mitochondrial content, fusion, and mitophagy. Thus, MICT but also HIIT (time-efficient training) could be recommended as exercise modalities for obese older adults to maintain or improve mobility, health and quality of life.

Parkin: a potential target to promote healthy ageing.

Parkin is an E3 ubiquitin ligase mostly known for its role in regulating the removal of defective mitochondria via mitophagy. However, increasing experimental evidence that Parkin regulates several other aspects of mitochondrial biology in addition to its role in mitophagy has emerged over the past two decades. Indeed, Parkin has been shown to regulate mitochondrial biogenesis and dynamics and mitochondria-derived vesicle formation, suggesting that Parkin plays key roles in maintaining healthy mitochondria. While Parkin is commonly described as a cytosolic E3 ubiquitin ligase, it was also detected in other cellular compartments, including the nucleus, where it regulates transcription factors and acts as a transcription factor itself. New evidence also suggests that Parkin overexpression can be leveraged to delay ageing. In Drosophila, for example, Parkin overexpression extends lifespan. In mammals, Parkin overexpression delays hallmarks of ageing in several tissues and cell types. Parkin overexpression also confers protection in various models of cellular senescence and neurological disorders closely associated with ageing, such as Alzheimer's and Parkinson's diseases. Recently, Parkin overexpression has also been shown to suppress tumour growth. In this review, we discuss newly emerging biological roles of Parkin as a modulator of cellular homeostasis, survival and healthy ageing, and we explore potential mechanisms through which Parkin exerts its beneficial effects on cellular health.

Impact of high-intensity interval training with or without l-citrulline on physical performance, skeletal muscle, and adipose tissue in obese older adults.

BACKGROUND: Aging is associated with a progressive decline in skeletal muscle mass and strength as well as an increase in adiposity. These changes may have devastating impact on the quality of life of older adults. Mitochondrial dysfunctions have been implicated in aging-related and obesity-related deterioration of muscle function. Impairments in mitochondrial quality control processes (biogenesis, fusion, fission, and mitophagy) may underlie this accumulation of mitochondrial dysfunction. High-intensity interval training (HIIT) was shown to improve muscle and mitochondrial function in healthy young and old adults and to improve body composition in obese older adults. Recent studies also positioned citrulline (CIT) supplementation as a promising intervention to counter obesity-related and aging-related muscle dysfunction. In the present study, our objectives were to assess whether HIIT, alone or with CIT, improves muscle function, functional capacities, adipose tissue gene expression, and mitochondrial quality control processes in obese older adults. METHODS: Eighty-one-old and obese participants underwent a 12 week HIIT with or without CIT on an elliptical trainer [HIIT-CIT: 20 men/25 women, 67.2 ± 5.0 years; HIIT-placebo (PLA): 18 men/18 women, 68.1 ± 4.1 years]. Handgrip and quadriceps strength, lower limb muscle power, body composition, waist circumference, and functional capacities were assessed pre and post intervention. Vastus lateralis muscle biopsies were performed in a subset of participants to quantify markers of mitochondrial content (TOM20 and OXPHOS subunits), biogenesis (TFAM), fusion (MFN1&2, OPA1), fission (DRP1), and mitophagy (Parkin). Subcutaneous abdominal adipose tissue biopsies were also performed to assess the expression of genes involved in lipid metabolism. RESULTS: HIIT-PLA and HIIT-CIT displayed improvements in functional capacities (P < 0.05), total (mean ± SD: HIIT-PLA: +1.27 ± 3.19%, HIIT-CIT: +1.05 ± 2.91%, P < 0.05) and leg lean mass (HIIT-PLA: +1.62 ± 3.85%, HIIT-CIT: +1.28 ± 4.82%, P < 0.05), waist circumference (HIIT-PLA: -2.2 ± 2.9 cm, HIIT-CIT: -2.6 ± 2.5 cm, P < 0.05), and muscle power (HIIT-PLA: +15.81 ± 18.02%, HIIT-CIT: +14.62 ± 20.02%, P < 0.05). Only HIIT-CIT decreased fat mass (-1.04 ± 2.42%, P < 0.05) and increased handgrip and quadriceps strength (+4.28 ± 9.36% and +10.32 ± 14.38%, respectively, P < 0.05). Both groups increased markers of muscle mitochondrial content, mitochondrial fusion, and mitophagy (P < 0.05). Only HIIT-CIT decreased the expression of the lipid droplet-associated protein CIDEA (P < 0.001). CONCLUSIONS: High-intensity interval training is effective in improving functional capacities, lean mass, muscle power, and waist circumference in obese older adults. HIIT also increases markers of mitochondrial biogenesis, mitochondrial fusion, and mitophagy. Importantly, adding CIT to HIIT results in a greater increase in muscle strength and a significant decrease in fat mass. The present study therefore positions HIIT combined with CIT as an effective intervention to improve the health status of obese older adults.

Human studies of mitochondrial biology demonstrate an overall lack of binary sex differences: A multivariate meta-analysis.

Mitochondria are maternally inherited organelles that play critical tissue-specific roles, including hormone synthesis and energy production, that influence human development, health, and aging. However, whether mitochondria from women and men exhibit consistent biological differences remains unclear, representing a major gap in knowledge. This meta-analysis systematically examined four domains and six subdomains of mitochondrial biology (total 39 measures), including mitochondrial content, respiratory capacity, reactive oxygen species (ROS) production, morphometry, and mitochondrial DNA copy number. Standardized effect sizes (Hedge's g) of sex differences were computed for each measure using data in 2258 participants (51.5% women) from 50 studies. Only two measures demonstrated aggregate binary sex differences: higher mitochondrial content in women's WAT and isolated leukocyte subpopulations (g = 0.20, χ2 p = .01), and higher ROS production in men's skeletal muscle (g = 0.49, χ2 p < .0001). Sex differences showed weak to no correlation with age or BMI. Studies with small sample sizes tended to overestimate effect sizes (r = -.17, p < .001), and sex differences varied by tissue examined. Our findings point to a wide variability of findings in the literature concerning possible binary sex differences in mitochondrial biology. Studies specifically designed to capture sex- and gender-related differences in mitochondrial biology are needed, including detailed considerations of physical activity and sex hormones.

Potential mechanisms involved in regulating muscle protein turnover after acute exercise: A brief review.

It is well established that resistance training increases muscle mass. Indeed, there is evidence to suggest that a single session of resistance training is associated with an increase in muscle protein synthesis in young adults. However, the fundamental mechanisms that are involved in regulating muscle protein turnover rates after an acute bout of physical exercise are unclear. Therefore, this review will briefly focus on summarizing the potential mechanisms behind the growth of skeletal muscle after physical exercise. We also present mechanistic differences that may exist between young and older individuals during muscle protein synthesis and breakdown after physical exercise. Pathways leading to the activation of AKT/mTOR signals after resistance exercise and the activation of AMPK signaling pathway following a HIIT (High intensity interval training) are discussed.

Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging.

The maintenance of mitochondrial integrity is critical for muscle health. Mitochondria, indeed, play vital roles in a wide range of cellular processes, including energy supply, Ca2+ homeostasis, retrograde signaling, cell death, and many others. All mitochondria-containing cells, including skeletal muscle cells, dispose of several pathways to maintain mitochondrial health, including mitochondrial biogenesis, mitochondrial-derived vesicles, mitochondrial dynamics (fusion and fission process shaping mitochondrial morphology), and mitophagy-the process in charge of the removal of mitochondria though autophagy. The loss of skeletal muscle mass (atrophy) is a major health problem worldwide, especially in older people. Currently, there is no treatment to counteract the progressive decline in skeletal muscle mass and strength that occurs with aging, a process termed sarcopenia. There is increasing data, including our own, suggesting that accumulation of dysfunctional mitochondria contributes to the development of sarcopenia. Impairments in mitochondrial dynamics and mitophagy were recently proposed to contribute to sarcopenia. This review summarizes the current state of knowledge on the role played by mitochondrial dynamics and mitophagy in skeletal muscle health and in the development of sarcopenia. We also highlight recent studies showing that enhancing mitophagy in skeletal muscle is a promising therapeutic target to prevent or even treat skeletal muscle dysfunction in the elderly.