Novel Multi-Ingredient Supplement Facilitates Weight Loss and Improves Body Composition in Overweight and Obese Individuals: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

BACKGROUND: Despite the growing recognition of the obesity crisis, its rates continue to rise. The current first-line therapies, such as dietary changes, energy restriction, and physical activity, are typically met with poor adherence. Novel nutritional interventions can address the root causes of obesity, including mitochondrial dysfunction, and facilitate weight loss. OBJECTIVE: The objective of this study was to investigate the effects of a multi-ingredient nutritional supplement designed to facilitate mitochondrial function and metabolic health outcomes over a 12 wk period. METHODS: Fifty-five overweight and/or obese participants (age (mean ± SEM): 26 ± 1; body mass index (BMI) (kg/m2): 30.5 ± 0.6) completed this double-blind, placebo-controlled clinical trial. Participants were randomized to 12 wks of daily consumption of multi-ingredient supplement (MIS; n = 28; containing 50 mg forskolin, 500 mg green coffee bean extract, 500 mg green tea extract, 500 mg beet root extract, 400 mg α-lipoic acid, 200 IU vitamin E, and 200 mg CoQ10) or control placebo (PLA, n = 27; containing microcrystalline cellulose) matched in appearance. The co-primary outcomes were bodyweight and fat mass (kg) changes. The secondary outcomes included other body composition measures, plasma markers of obesity, fatty liver disease biomarkers, resting energy metabolism, blood pressure, physical performance, and quality of life. The post-intervention differences between MIS and PLA were examined via ANCOVA which was adjusted for the respective pre-intervention variables. RESULTS: After adjustment for pre-intervention data, there was a significant difference in weight (p < 0.001) and fat mass (p < 0.001) post-intervention between the PLA and MIS treatment arms. Post-intervention weight and fat mass were significantly lower in MIS. Significant post-intervention differences corrected for baseline were found in markers of clinical biochemistry (AST, p = 0.017; ALT, p = 0.008), molecular metabolism (GDF15, p = 0.028), and extracellular vesicle-associated miRNA species miR-122 and miR-34a in MIS (p < 0.05). CONCLUSIONS: Following the 12 wks of MIS supplementation, weight and body composition significantly improved, concomitant with improvements in molecular markers of liver health and metabolism.

Circulating exosome-like vesicle and skeletal muscle microRNAs are altered with age and resistance training.

The age-related loss of skeletal muscle mass and functionality, known as sarcopenia, is a critical risk factor for morbidity and all-cause mortality. Resistance exercise training (RET) is the primary countermeasure to fight sarcopenia and ageing. Altered intercellular communication is a hallmark of ageing, which is not well elucidated. Circulating extracellular vesicles (EVs), including exosomes, contribute to intercellular communication by delivering microRNAs (miRNAs), which modulate post-translational modifications, and have been shown to be released following exercise. There is little evidence regarding how EVs or EV-miRNAs are altered with age or RET. Therefore, we sought to characterize circulating EVs in young and older individuals, prior to and following a 12-week resistance exercise programme. Plasma EVs were isolated using size exclusion chromatography and ultracentrifugation. We found that ageing reduced circulating expression markers of CD9, and CD81. Using late-passage human myotubes as a model for ageing in vitro, we show significantly lower secreted exosome-like vesicles (ELVs). Further, levels of circulating ELV-miRNAs associated with muscle health were lower in older individuals at baseline but increased following RET to levels comparable to young. Muscle biopsies show similar age-related reductions in miRNA expressions, with largely no effect of training. This is reflected in vitro, where aged myotubes show significantly reduced expression of endogenous and secreted muscle-specific miRNAs (myomiRs). Lastly, proteins associated with ELV and miRNA biogenesis were significantly higher in both older skeletal muscle tissues and aged human myotubes. Together we show that ageing significantly affects ELV and miRNA cargo biogenesis, and release. RET can partially normalize this altered intercellular communication. KEY POINTS: We show that ageing reduces circulating expression of exosome-like vesicle (ELV) markers, CD9 and CD81. Using late-passage human skeletal myotubes as a model of ageing, we show that secreted ELV markers are significantly reduced in vitro. We find circulating ELV miRNAs associated with skeletal muscle health are lower in older individuals but can increase following resistance exercise training (RET). In skeletal muscle, we find altered expression of miRNAs in older individuals, with no effect of RET. Late-passage myotubes also appear to have aberrant production of endogenous myomiRs with lower abundance than youthful counterparts In older skeletal muscle and late-passage myotubes, proteins involved with ELV- and miRNA biogenesis are upregulated.

Short-term aerobic conditioning prior to resistance training augments muscle hypertrophy and satellite cell content in healthy young men and women.

Factors influencing inter-individual variability of responses to resistance training (RT) remain to be fully elucidated. We have proposed the importance of capillarization in skeletal muscle for the satellite cell (SC) response to RT-induced muscle hypertrophy, and hypothesized that aerobic conditioning (AC) would augment RT-induced adaptations. Fourteen healthy young (22 ± 2 years) men and women underwent AC via 6 weeks of unilateral cycling followed by 10 weeks of bilateral RT to investigate how AC alters SC content, activity, and muscle hypertrophy following RT. Muscle biopsies were taken at baseline (unilateral), post AC (bilateral), and post RT (bilateral) in the aerobically conditioned (AC + RT) and unconditioned (RT) legs. Immunofluorescence was used to determine muscle capillarization, fiber size, SC content, and activity. Type I and type II fiber cross-sectional area (CSA) increased following RT, and when legs were analyzed independently, AC + RT increased type I, type II, and mixed-fiber CSA, where the RT leg tended to increase type II (p = .05), but not type I or mixed-fiber CSA. SC content, activation, and differentiation increased with RT, where type I total and quiescent SC content was greater in AC + RT compared to the RT leg. Those with the greatest capillary-to-fiber perimeter exchange index before RT had the greatest change in CSA following RT and a significant relationship was observed between type II fiber capillarization and the change in type II-fiber CSA with RT (r = 0.35). This study demonstrates that AC prior to RT can augment RT-induced muscle adaptions and that these differences are associated with increases in capillarization.

Nutritional co-therapy with 1,3-butanediol and multi-ingredient antioxidants enhances autophagic clearance in Pompe disease.

Alglucosidase alpha is an orphan drug approved for enzyme replacement therapy (ERT) in Pompe disease (PD); however, its efficacy is limited in skeletal muscle because of a partial blockage of autophagic flux that hinders intracellular trafficking and enzyme delivery. Adjunctive therapies that enhance autophagic flux and protect mitochondrial integrity may alleviate autophagic blockage and oxidative stress and thereby improve ERT efficacy in PD. In this study, we compared the benefits of ERT combined with a ketogenic diet (ERT-KETO), daily administration of an oral ketone precursor (1,3-butanediol; ERT-BD), a multi-ingredient antioxidant diet (ERT-MITO; CoQ10, α-lipoic acid, vitamin E, beetroot extract, HMB, creatine, and citrulline), or co-therapy with the ketone precursor and multi-ingredient antioxidants (ERT-BD-MITO) on skeletal muscle pathology in GAA-KO mice. We found that two months of 1,3-BD administration raised circulatory ketone levels to ≥1.2 mM, attenuated autophagic buildup in type 2 muscle fibers, and preserved muscle strength and function in ERT-treated GAA-KO mice. Collectively, ERT-BD was more effective vs. standard ERT and ERT-KETO in terms of autophagic clearance, dampening of oxidative stress, and muscle maintenance. However, the addition of multi-ingredient antioxidants (ERT-BD-MITO) provided the most consistent benefits across all outcome measures and normalized mitochondrial protein expression in GAA-KO mice. We therefore conclude that nutritional co-therapy with 1,3-butanediol and multi-ingredient antioxidants may provide an alternative to ketogenic diets for inducing ketosis and enhancing autophagic flux in PD patients.

Aerobic exercise elicits clinical adaptations in myotonic dystrophy type 1 patients independently of pathophysiological changes.

BackgroundMyotonic dystrophy type 1 (DM1) is a complex life-limiting neuromuscular disorder characterized by severe skeletal muscle atrophy, weakness, and cardiorespiratory defects. Exercised DM1 mice exhibit numerous physiological benefits that are underpinned by reduced CUG foci and improved alternative splicing. However, the efficacy of physical activity in patients is unknown.MethodsEleven genetically diagnosed DM1 patients were recruited to examine the extent to which 12 weeks of cycling can recuperate clinical and physiological metrics. Furthermore, we studied the underlying molecular mechanisms through which exercise elicits benefits in skeletal muscle of DM1 patients.RESULTSDM1 was associated with impaired muscle function, fitness, and lung capacity. Cycling evoked several clinical, physical, and metabolic advantages in DM1 patients. We highlight that exercise-induced molecular and cellular alterations in patients do not conform with previously published data in murine models and propose a significant role of mitochondrial function in DM1 pathology. Finally, we discovered a subset of small nucleolar RNAs (snoRNAs) that correlated to indicators of disease severity.ConclusionWith no available cures, our data support the efficacy of exercise as a primary intervention to partially mitigate the clinical progression of DM1. Additionally, we provide evidence for the involvement of snoRNAs and other noncoding RNAs in DM1 pathophysiology.Trial registrationThis trial was approved by the HiREB committee (no. 7901) and registered under ClinicalTrials.gov (NCT04187482).FundingNeil and Leanne Petroff. Canadian Institutes of Health Research Foundation (no. 143325).

A Novel Multi-Ingredient Supplement Activates a Browning Program in White Adipose Tissue and Mitigates Weight Gain in High-Fat Diet-Fed Mice.

We investigated the effects of a novel multi-ingredient supplement comprised of polyphenol antioxidants and compounds known to facilitate mitochondrial function and metabolic enhancement (ME) in a mouse model of obesity. In this study, 6-week-old male C57/BL6J mice were placed on a high-fat diet (HFD; ~60% fat) for 6 weeks, with subsequent allocation into experimentalgroups for 4 weeks: HFD control, HFD + ME10 (10 components), HFD + ME7 (7 components), HFD + ME10 + EX, HFD + EX (where '+EX' animals exercised 3 days/week), and chow-fed control. After the intervention, HFD control animals had significantly greater body weight and fat mass. Despite the continuation of HFD, animals supplemented with multi-ingredient ME or who performed exercise training showed an attenuation of fat mass and preservation of lean body mass, which was further enhanced when combined (ME+EX). ME supplementation stimulated the upregulation of white and brown adipose tissue mRNA transcripts associated with mitochondrial biogenesis, browning, fatty acid transport, and fat metabolism. In WAT depots, this was mirrored by mitochodrial oxidative phosphorylation (OXPHOS) protein expression, and increased in vivo fat oxidation measured via CLAMS. ME supplementation also decreased systemic and local inflammation markers. Herein, we demonstrated that novel multi-ingredient nutritional supplements induced significant fat loss independent of physical activity while preserving muscle mass in obese mice. Mechanistically, these MEs appear to act by inducing a browning program in white adipose tissue and decreasing other pathophysiological impairments associated with obesity, including mitochondrial respiration alterations induced by HFD.

Age-related changes to the satellite cell niche are associated with reduced activation following exercise.

Skeletal muscle satellite cell (SC) function and responsiveness is regulated, in part, through interactions within the niche, in which they reside. Evidence suggests that structural changes occur in the SC niche as a function of aging. In the present study, we investigated the impact of aging on SC niche properties. Muscle biopsies were obtained from the vastus lateralis of healthy young (YM; 21 ± 1 yr; n = 10) and older men (OM; 68 ± 1 yr; n = 16) at rest. A separate group of OM performed a single bout of resistance exercise and additional muscle biopsies were taken 24 and 48 hours post-exercise; this was performed before and following 12 wks of combined exercise training (OM-Ex; 73 ± 1; n = 24). Muscle SC niche measurements were assessed using high resolution immunofluorescent confocal microscopy. Type II SC niche laminin thickness was greater in OM (1.86 ± 0.06 µm) as compared to YM (1.55 ± 0.09 µm, P < .05). The percentage of type II-associated SC that were completely surrounded by laminin was greater in OM (13.6%±4.2%) as compared to YM (3.5%±1.5%; P < .05). In non-surrounded SC, the proportion of active MyoD+ /Pax7+ SC were higher compared to surrounded SC (P < .05) following a single bout of exercise. This "incarceration" of the SC niche by laminin appears with aging and may inhibit SC activation in response to exercise.