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This study aimed to investigate the direct influence of a decrease in the cellular thiamin level, before the onset of anorexia (one of the symptoms of thiamin deficiency) on glycogen metabolism and the AMP-activated protein kinase (AMPK) activation levels in skeletal muscle at rest and in response to exercise. Male Wistar rats were classified as the control diet (CON) group or the thiamin-deficient diet (TD) group and consumed the assigned diets for 1 week. Skeletal muscles were taken from the rats at rest, those that underwent low-intensity swimming (LIS), or high-intensity intermittent swimming (HIS) conducted immediately before dissection. There were no significant differences in food intake, locomotive activity, or body weight between groups, but thiamin pyrophosphate in the skeletal muscles of the TD group was significantly lower than that of the CON group. Muscle glycogen and lactate levels in the blood and muscle were equivalent between groups at rest and in response to exercise. The mitochondrial content was equal between groups, and AMPK in the skeletal muscles of TD rats was normally activated by LIS and HIS. In conclusion, with a lowered cellular thiamin level, the exercise-associated glycogen metabolism and AMPK activation level in skeletal muscle were normally regulated.

The responses to Antihypertensive drugs vary among patients. The renal and muscular processes of blood flow regulation in peripheral blood vessels depend on the genetic and physiological constitution. Here, we present a case of an elderly female patient who experienced several phases of hypertensive emergencies during supervised training sessions. Hypertension treatment with different ACE inhibitors was discontinued because of severe side effects or simply no effect. Genotyping of ACE and ACTN3 gene polymorphisms helped find adequate antihypertensive treatment after all other approaches failed. The measured ACTN3-RR genotype indicated the possibility of a higher proportion of fast-twitch muscle fibers. This type of muscle fiber contributes to the generation of a high muscle force, which can compress the vascular bed more during physical work than slow muscle fibers. Therefore, a beta-blocker was used for treatment, allowing better vasodilative capacity. As reported by the patient, this pharmaceutical alone helped treat hypertensive emergencies adequately. Therefore, we believe that genetic information can help to identify optimal pharmaceutical treatments a problem that is highly prevalent in elderly subjects.

As a major site of glucose uptake following a meal, skeletal muscle has an important role in whole-body glucose metabolism. Evidence in humans and animal models of insulin resistance and type 2 diabetes suggests that alterations in mitochondrial characteristics accompany the development of skeletal muscle insulin resistance. However, it is unclear whether changes in mitochondrial content, respiratory function, or substrate oxidation are central to the development of insulin resistance or occur in response to insulin resistance. Thus, this review will aim to evaluate the apparent conflicting information placing mitochondria as a key organelle in the development of insulin resistance in skeletal muscle.

The asymptote (critical power; CP) and curvature constant (W') of the hyperbolic power–duration relationship can predict performance within the severe‐intensity exercise domain. However, the extent to which these parameters relate to skeletal muscle mitochondrial content and respiratory function is not known. Fifteen males (peak O2 uptake, 52.2 ± 8.7 mL kg−1 min−1; peak work rate, 366 ± 40 W; and gas exchange threshold, 162 ± 41 W) performed three to five constant‐load tests to task failure for the determination of CP (246 ± 44 W) and W' (18.6 ± 4.1 kJ). Skeletal muscle biopsies were obtained from the vastus lateralis to determine citrate synthase (CS) activity, as a marker of mitochondrial content, and the ADP‐stimulated respiration (P) and maximal electron transfer (E) through mitochondrial complexes (C) I–IV. The CP was positively correlated with CS activity (absolute CP, r = 0.881, P < 0.001; relative CP, r = 0.751, P = 0.001). The W' was not correlated with CS activity (P > 0.05). Relative CP was positively correlated with mass‐corrected CI + IIE (r = 0.659, P = 0.038), with absolute CP being inversely correlated with CS activity‐corrected CIVE (r = −0.701, P = 0.024). Relative W' was positively correlated with CS activity‐corrected CI + IIP (r = 0.713, P = 0.021) and the phosphorylation control ratio (r = 0.661, P = 0.038). There were no further correlations between CP or W' and mitochondrial respiratory variables. These findings support the assertion that skeletal muscle mitochondrial oxidative capacity is positively associated with CP and that this relationship is strongly determined by mitochondrial content. What is the central question of this study? The asymptote (critical power; CP) and curvature constant (W') of the hyperbolic power–duration relationship are important determinants of severe‐intensity exercise performance. We assessed the relationship between these parameters and skeletal muscle mitochondrial content and respiration. What us the main finding and its importance? Citrate synthase (CS) activity was positively correlated with CP. Relative CP was positively correlated with mass‐corrected CI + IIE; absolute CP was inversely correlated with CS activity‐corrected CIVE. CS activity was not correlated with W'. CS activity‐corrected CI + IIP and the phosphorylation control ratio were positively correlated with relative W'. Mitochondrial content influences CP. Some facets of mitochondrial respiration might influence W'.

This review provides an overview of the evidence regarding mtDNA and valid biomarkers for assessing mitochondrial adaptions. Mitochondria are small organelles that exist in almost all cells throughout the human body. As the only organelle, mitochondria contain their own DNA, mitochondrial DNA (mtDNA). mtDNA-encoded polypeptides are subunits of the enzyme complexes in the electron transport chain (ETC) that are responsible for production of ATP to the cells. mtDNA is frequently used as a biomarker for mitochondrial content, since changes in mitochondrial volume are thought to induce similar changes in mtDNA. However, some exercise studies have challenged this “gene-dosage theory”, and have indicated that changes in mitochondrial content can adapt without changes in mtDNA. Thus, the aim of this scoping review was to summarize the studies that used mtDNA as a biomarker for mitochondrial adaptions and address the question as to whether changes in mitochondrial content, induce changes in mtDNA in response to aerobic exercise in the healthy skeletal muscle. The literature was searched in PubMed and Embase. Eligibility criteria included: interventional study design, aerobic exercise, mtDNA measurements reported pre- and postintervention for the healthy skeletal muscle and English language. Overall, 1585 studies were identified. Nine studies were included for analysis. Eight out of the nine studies showed proof of increased oxidative capacity, six found improvements in mitochondrial volume, content and/or improved mitochondrial enzyme activity and seven studies did not find evidence of change in mtDNA copy number. In conclusion, the findings imply that mitochondrial adaptions, as a response to aerobic exercise, can occur without a change in mtDNA copy number.

Background Mitochondrial genome copy number (MT-CN) varies among humans and across tissues and is highly heritable, but its causes and consequences are not well understood. When measured by bulk DNA sequencing in blood, MT-CN may reflect a combination of the number of mitochondria per cell and cell-type composition. Here, we studied MT-CN variation in blood-derived DNA from 19184 Finnish individuals using a combination of genome (N = 4163) and exome sequencing (N = 19034) data as well as imputed genotypes (N = 17718). Results We identified two loci significantly associated with MT-CN variation: a common variant at the MYB-HBS1L locus (P = 1.6 × 10 −8 ), which has previously been associated with numerous hematological parameters; and a burden of rare variants in the TMBIM1 gene (P = 3.0 × 10 −8 ), which has been reported to protect against non-alcoholic fatty liver disease. We also found that MT-CN is strongly associated with insulin levels (P = 2.0 × 10 −21 ) and other metabolic syndrome (metS)-related traits. Using a Mendelian randomization framework, we show evidence that MT-CN measured in blood is causally related to insulin levels. We then applied an MT-CN polygenic risk score (PRS) derived from Finnish data to the UK Biobank, where the association between the PRS and metS traits was replicated. Adjusting for cell counts largely eliminated these signals, suggesting that MT-CN affects metS via cell-type composition. Conclusion These results suggest that measurements of MT-CN in blood-derived DNA partially reflect differences in cell-type composition and that these differences are causally linked to insulin and related traits.

The effect of biological sex on rates of skeletal muscle mitochondrial respiration supported by creatine‐dependent phosphate shuttling was previously unknown. The aim of this investigation was to test the hypothesis that females and males matched for peak oxygen uptake normalized to fat‐free mass would not exhibit differences in rates of mass‐specific and intrinsic mitochondrial respiration in the presence or absence of creatine. Rates of mass‐specific and intrinsic complex I (pyruvate and malate)‐ and complex I+II‐supported, adenosine diphosphate (ADP)‐stimulated mitochondrial respiration in the presence and absence of 20 mM creatine were measured via high‐resolution respirometry. Total, intermyofibrillar and subsarcolemmal mitochondrial volume density were analysed using transmission electron microscopy. Rates of intrinsic mitochondrial respiration were obtained by normalizing mass‐specific respiration rates to total mitochondrial volume density and total electron transport chain subunit protein content. Overall, there was no effect of sex on rates of mass‐specific or intrinsic mitochondrial respiration in the presence or absence of creatine. There was also no effect of sex on total, intermyofibrillar and subsarcolemmal mitochondrial volume density or electron transport chain subunit protein content. Our data demonstrate an overall lack of sex‐based differences in rates of intrinsic complex I‐ and complex I+II‐supported, ADP‐stimulated mitochondrial respiration in the presence or absence of creatine in females and males matched for aerobic fitness. Thus, biological sex per se does not appear to modulate intrinsic skeletal muscle mitochondrial respiration in healthy young adults. What is the central question of this study? Mitochondrial–cytosolic energy exchange can occur via creatine‐dependent and ‐independent mechanisms, but whether biological sex impacts rates of intrinsic mitochondrial respiration in the presence of creatine in human skeletal muscle remains unknown. What is the main finding and its importance? Biological sex does not impact mitochondrial volume density or intrinsic mitochondrial respiration supported by creatine‐dependent phosphate shuttling and creatine‐independent ADP diffusion when females and males are matched for peak oxygen uptake normalized to fat‐free mass. Matching females and males for aerobic fitness mitigates sex differences in rates of mitochondrial respiration and mitochondrial content in humans.

The present study aimed to determine the impact of colon 26 adenocarcinoma (C26)-induced cancer cachexia on skeletal muscle mitochondrial respiration and content. Twelve male CD2F1 mice were injected with C26-cells (tumor bearing (TB) group), whereas 12 age-matched mice received PBS vehicle injection (non-tumor bearing (N-TB) group). Mitochondrial respiration was studied in saponin-permeabilized soleus myofibers. TB mice showed lower body weight (~ 20%) as well as lower soleus, gastrocnemius-plantaris complex and tibialis anterior masses versus N-TB mice (p < 0.05). Soleus maximal state III mitochondrial respiration was 20% lower (10 mM glutamate, 5 mM malate, 5 mM adenosine diphosphate; p < 0.05) and acceptor control ratio (state III/state II) was 15% lower in the TB vs. N-TB (p < 0.05), with the latter suggesting uncoupling. Lower VDAC protein content suggested reduced mitochondrial content in TB versus N-TB (p < 0.05). Skeletal muscle in C26-induced cancer cachexia exhibits reductions in: maximal mitochondrial respiration capacity, mitochondrial coupling and mitochondrial content.

Intrauterine growth restriction (IUGR) affects 5–10% of pregnancies with placental hypoxia, playing a key role as a common pathophysiological pathway of different etiologies. Despite the high metabolic rate of the placenta and its “gatekeeper” role in protecting the fetus from hypoxia, the response of placental mitochondria to hypoxic stress is not well understood. This study tested the hypothesis that transient exposure to hypoxia leads to a loss of placental mitochondria and affects their function. Human villous trophoblastic (JEG-3) cells were cultured under normoxic and hypoxic conditions for 24 h. Mitochondrial content was determined by flow cytometry before and after hypoxic exposure and after 24 h of normoxic recovery. Parameters of oxidative phosphorylation were assessed using a respirometric analyzer before hypoxic exposure and after normoxic recovery. Mitochondrial content decreased significantly from 88.5% to 26.7% during hypoxic incubation. Although it had increased to 84.2% after 24 h of normoxic recovery, oxidative phosphorylation parameters were still significantly suppressed to 1/2 to 1/3 of the pre-incubation levels. The results underscore the ability of placental cells to adapt mitochondrial content to O2 supply. Despite rapid recovery under normoxia, respiratory function remains suppressed, which may result in persistent impairment of adenosine triphosphate (ATP)-dependent synthetic and transport functions.

Mitochondria, classically known as the powerhouse of cells, are unique double membrane-bound multifaceted organelles carrying a genome. Mitochondrial content varies between cell types and precisely doubles within cells during each proliferating cycle. Mitochondrial content also increases to a variable degree during cell differentiation triggered after exit from the proliferating cycle. The mitochondrial content is primarily maintained by the regulation of mitochondrial biogenesis, while damaged mitochondria are eliminated from the cells by mitophagy. In any cell with a given mitochondrial content, the steady-state mitochondrial number and shape are determined by a balance between mitochondrial fission and fusion processes. The increase in mitochondrial content and alteration in mitochondrial fission and fusion are causatively linked with the process of differentiation. Here, we critically review the quantitative aspects in the detection methods of mitochondrial content and shape. Thereafter, we quantitatively link these mitochondrial properties in differentiating cells and highlight the implications of such quantitative link on stem cell functionality. Finally, we discuss an example of cell size regulation predicted from quantitative analysis of mitochondrial shape and content. To highlight the significance of quantitative analyses of these mitochondrial properties, we propose three independent rationale based hypotheses and the relevant experimental designs to test them.