Gnaiger 2019 MiP2019
Gnaiger E (2019)
“Preventable diseases are strongly related to a sedentary life style. These are spreading world-wide at an epidemic scale. Mitochondrial dysfunction is increasingly associated with the progression of such pathologies: cause or consequence? There is currently no regimented, quantitative system, or database organized to routinely test, compare and monitor mitochondrial capacities within individuals, populations, or among populations. This reflects the need for scientific innovation and represents a shortcoming in the health system of our modern, rapidly aging society” (MitoEAGLE COST Action application). The working groups of the COST Action CA15203 have made substantial progress towards meeting the mission of Mitochondrial Fitness Mapping (Fig. 1). The present communication (1) provides an example of harmonization of datasets published by different research laboratories on OXPHOS capacity in isolated mitochondria and permeabilized fibers obtained from biopsies of human skeletal muscle (vastus lateralis); (2) emphasizes the importance of comparative protocol harmonization projects and reproducibility studies; (3) illustrates the necessity and difficulty of defining objective exclusion criteria and applying quality assessment of published data; (4) links muscle mitochondrial fitness to whole body aerobic fitness; (5) discusses the extension of tissue-specific to systemic mitochondrial fitness from muscle to brain; and (6) documents the added value of Open Access data repositories.
Analogous to ergometric measurement of VO2max on a cycle or treadmill, cell ergometry is based on measurement of OXPHOS-capacity, JO2,P [pmol O2·s-1·mg-1] equivalent to [µmol O2·s1·kg1], at the mitochondrial level. The main datasets on OXPHOS capacity of isolated mitochondria or permeabilized muscle fibers, harmonization algorithms, and exclusion criteria applied in the present analysis have been reviewed ten years ago . Only a few more studies based on high-resolution respirometry published since then were integrated, exclusively on Caucasian healthy controls [2,3]. This 'MitoEAGLE database 1' is intended to initiate a comprehensive review by the MitoEAGLE Working Group 2 (skeletal muscle). Harmonization introduces potential biases with a scope of improvement based on updated evaluation of (1) wet/dry mass ratios applicable to studies reporting dry mass only; (2) flux control ratios applied to calculate combined NADH- and succinate-linked OXPHOS capacities from data limited to the NADH-pathway or succinate-pathway capacities measured separately; (3) temperature adjustment for measurements at temperatures different from 37 °C ; (4) oxygen limitation of measurements with permeabilized fibers that are performed at or below air saturation ; (5) OXPHOS capacities reported without evaluation of saturating concentrations of ADP, Pi, and fuel substrates, or without concern of stable steady-state fluxes; and (6) potential bias when results are reported without details on instrumental O2-background tests, calibrations, and corresponding corrections.
Recent trends of an increasing body mass index (BMI) of the human population indicate an epidemic prevalence of obesity in many countries despite the fact that underweight remains the dominant problem in the world’s poorest regions . Extending the concept of the ‘Reference Man’ , a healthy reference population (HRP) is defined with a large range of body height (standing height, h) and corresponding reference body mass, m°, reference VO2max°, and mitochondrial fitness parameters (Fig. 2). The reference mass/height relationship constitutes a basic component of the concept of the HRP, obtained from >17.000 measurements on healthy people reported between 1931 and 1944 before the fast food and soft drink epidemic, with about half of the reported measurements ranging from 1.2 to 1.8 m corresponding to m° of 22 to 68 kg and h/m0.35  (Fig. 2a).
The body mass excess, BME, is defined as the actual body mass, m, relative to the reference body mass, m°, at the same height (Suppl. Tab. S1). Deviations of m versus m° are due to weight gain without height gain. The similar displacement of men and women (Norwegian HUNT 3 study ) from the HRP line is consistent with the increase of average BMI in Norway during the past decades . (Fig. 2a). BME>1 (excess) yields a more consistent index of overweight and obesity across a large range of body heights compared to the BMI (Fig. 2b). Similarly, BME<1 (not shown) indicates a body mass deficit which is insufficiently reflected by the BMI at different body heights. Mitochondrial OXPHOS capacity per mass of vastus lateralis declines as a power function of BME (Fig. 2c). VO2max/BM can be modeled as a function of (1) the metabolically inactive (compared to VO2max) body mass added to a person at height h, (2) the decline of mitochondrial capacity per muscle mass as a consequence of an inactive lifestyle and increased body mass, and (3) a slight increase of muscle mass with increasing BME as a ‘weight lifting effect’ (Fig. 2d).
Taken together, the BME has a strong conceptual foundation on the level of large scale population statistics and is linked to lifestyle and mitochondrial fitness. Importantly, the BME has a straightforward understandable meaning that is easy to communicate to the general public on the personal level: you are overweight if your body mass is increased by 20 to 25 % relative to the reference body mass determined by your height. The consequences of mitochondrial control on VO2max/BM will be discussed in terms of mechanistic explanations of a large range of neurodegenerative diseases related to the passive lifestyle with an increased BME .
• Keywords: healthy reference population - HRP, body mass index - BMI, body mass excess - BME, aerobic capacity - VO2max per body mass, mitochondrial fitness • Bioblast editor: Plangger M, Tindle-Solomon L, Gnaiger E • O2k-Network Lab: AT Innsbruck Gnaiger E, AT Innsbruck Oroboros
Labels: MiParea: Respiration, mt-Biogenesis;mt-density, Gender, Exercise physiology;nutrition;life style, mt-Medicine Pathology: Obesity
Organism: Human Tissue;cell: Skeletal muscle Preparation: Intact organism, Permeabilized tissue, Isolated mitochondria
Coupling state: OXPHOS Pathway: NS HRR: Oxygraph-2k
- Oroboros Instruments, Innsbruck, Austria
- Dept Visceral, Transplant Thoracic Surgery, Daniel Swarovski Research Lab, Medical Univ Innsbruck, Austria
- Gnaiger E (2009) Capacity of oxidative phosphorylation in human skeletal muscle. New perspectives of mitochondrial physiology. Int J Biochem Cell Biol 41:1837-45. - »Bioblast link«
- Pesta D, Hoppel F, Macek C, Messner H, Faulhaber M, Kobel C, Parson W, Burtscher M, Schocke M, Gnaiger E (2011) Similar qualitative and quantitative changes of mitochondrial respiration following strength and endurance training in normoxia and hypoxia in sedentary humans. Am J Physiol Regul Integr Comp Physiol 301:R1078–87. - »Bioblast link«
- Gnaiger E, Boushel R, Søndergaard H, Munch-Andersen T, Damsgaard R, Hagen C, Díez-Sánchez C, Ara I, Wright-Paradis C, Schrauwen P, Hesselink M, Calbet JAL, Christiansen M, Helge JW, Saltin B (2015) Mitochondrial coupling and capacity of oxidative phosphorylation in skeletal muscle of Inuit and caucasians in the arctic winter. Scand J Med Sci Sports 25 (Suppl 4):126–34. - »Bioblast link«
- Lemieux H, Blier PU, Gnaiger E (2017) Remodeling pathway control of mitochondrial respiratory capacity by temperature in mouse heart: electron flow through the Q-junction in permeabilized fibers. Sci Rep 7:2840. - »Bioblast link«
- Pesta D, Gnaiger E (2012) High-resolution respirometry. OXPHOS protocols for human cells and permeabilized fibres from small biopsies of human muscle. Methods Mol Biol 810:25-58. - »Bioblast link«
- NCD Risk Factor Collaboration (NCD-RisC) (2017) Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128·9 million children, adolescents, and adults. Lancet 390:2627–42.
- Sender R, Fuchs S, Milo R (2016) Revised estimates for the number of human and bacteria cells in the body. PLoS Biol 14:e1002533.
- Zucker TF (1962) Regression of standing and sitting weights on body weight: man. In: Altman PL, Dittmer DS, eds: Growth including reproduction and morphological development. Committee on Biological Handbooks, Fed Amer Soc Exp Biol:336-7.
- Loe H, Rognmo Ø, Saltin B, Wisløff U (2013) Aerobic capacity reference data in 3816 healthy men and women 20-90 years. PLoS One 8:e64319.
- Gnaiger E (2019) Body mass excess associated with decline of aerobic capacity and mitochondrial fitness. MitoFit Preprint Arch doi:10.26124/mitofit:190004 (in prep).
Figure 1. Challenges for initiation of a data repository designed to ultimately describe the linkage between the mt-phenotype and anthropometric variables. Modified after MitoEAGLE COST Action application.
- body mass excess with respect to the HRP is defined as BME ≝ m/m°. A balanced BME is BME°=1.0. Considering a height of 1.7 m (dashed horizontal lines), overweight (BMI=25) is reached at a weight gain of 25 % (BME=1.25); obesity and severe obesity (BMI=30 and 35) are reached at a weight gain of 50 % and 75 % (BME=1.5 and 1.75, respectively). (c) Mitochondrial fitness, JO2,P declines as a function of BME (MitoFit database 1). JO2,P is the OXPHOS capacity of the convergent NADH- and succinate-linked pathway expressed per wet mass of muscle tissue. (d) VO2max/BM declines as a function of BME (MitoFit database 1; a powerfunction is fitted through the open circles, shown by the full line and extrapolated to BME=1; see equation). The females of the HUNT 3 study are on the line, whereas the males tend to have a higher aerobic capacity. Dashed line (1): Aerobic capacity modelled by adding metabolically inactive body mass to the reference VO2max/BM°=72.7 mL∙min-1∙kg-1. Dottel line (2): Diminishing muscle aerobic capacity according to the decline of mitochondrial fitness in Fig. 2c. Red crosses (3): A constant ‘weight lifting factor’ is fitted to account for an increasing fraction of muscle mass as a function of body mass. Modified from .