Mitochondrial involvement in sarcopenia.

Sarcopenia lowers the quality-of-life for millions of people across the world, as accelerated loss of skeletal muscle mass and function contributes to both age- and disease-related frailty. Physical activity remains the only proven therapy for sarcopenia to date, but alternatives are much sought after to manage this progressive muscle disorder in individuals who are unable to exercise. Mitochondria have been widely implicated in the etiology of sarcopenia and are increasingly suggested as attractive therapeutic targets to help restore the perturbed balance between protein synthesis and breakdown that underpins skeletal muscle atrophy.

Acute bioenergetic insulin sensitivity of skeletal muscle cells: ATP-demand-provoked glycolysis contributes to stimulation of ATP supply.

Skeletal muscle takes up glucose in an insulin-sensitive manner and is thus important for the maintenance of blood glucose homeostasis. Insulin resistance during development of type 2 diabetes is associated with decreased ATP synthesis, but the causality of this association is controversial. In this paper, we report real-time oxygen uptake and medium acidification data that we use to quantify acute insulin effects on intracellular ATP supply and ATP demand in rat and human skeletal muscle cells.

Mitochondrial Activity and Skeletal Muscle Insulin Resistance in Kidney Disease.

Insulin resistance is a key feature of the metabolic syndrome, a cluster of medical disorders that together increase the chance of developing type 2 diabetes and cardiovascular disease. In turn, type 2 diabetes may cause complications such as diabetic kidney disease (DKD). Obesity is a major risk factor for developing systemic insulin resistance, and skeletal muscle is the first tissue in susceptible individuals to lose its insulin responsiveness.

Control of pancreatic β-cell bioenergetics.

The canonical model of glucose-stimulated insulin secretion (GSIS) by pancreatic β-cells predicts a glucose-induced rise in the cytosolic ATP/ADP ratio. Such bioenergetic sensitivity to metabolic fuel is unusual as it implies that ATP flux is governed, to a significant extent, by ATP supply, while it is predominantly demand-driven in other cell types. Metabolic control is generally shared between different processes, but potential control of ATP consumption over β-cell bioenergetics has been largely ignored to date.

Improved Survival in a Long-Term Rat Model of Sepsis Is Associated With Reduced Mitochondrial Calcium Uptake Despite Increased Energetic Demand.

Objectives: To investigate the relationship between prognosis, changes in mitochondrial calcium uptake, and bioenergetic status in the heart during sepsis.

Design: In vivo and ex vivo controlled experimental studies.

Setting: University research laboratory.

Skeletal muscle dysfunction is associated with derangements in mitochondrial bioenergetics (but not UCP3) in a rodent model of sepsis.

Muscle dysfunction is a common feature of severe sepsis and multiorgan failure. Recent evidence implicates bioenergetic dysfunction and oxidative damage as important underlying pathophysiological mechanisms. Increased abundance of uncoupling protein-3 (UCP3) in sepsis suggests increased mitochondrial proton leak, which may reduce mitochondrial coupling efficiency but limit reactive oxygen species (ROS) production.

Liver dysfunction and phosphatidylinositol-3-kinase signalling in early sepsis: experimental studies in rodent models of peritonitis.

Background: Hepatic dysfunction and jaundice are traditionally viewed as late features of sepsis and portend poor outcomes. We hypothesized that changes in liver function occur early in the onset of sepsis, yet pass undetected by standard laboratory tests.

Methods And Findings: In a long-term rat model of faecal peritonitis, biotransformation and hepatobiliary transport were impaired, depending on subsequent disease severity, as early as 6 h after peritoneal contamination.

Early functional and transcriptomic changes in the myocardium predict outcome in a long-term rat model of sepsis.

Myocardial function is depressed in sepsis and is an important prognosticator in the human condition. Using echocardiography in a long-term fluid-resuscitated Wistar rat model of faecal peritonitis we investigated whether depressed myocardial function could be detected at an early stage of sepsis and, if so, whether the degree of depression could predict eventual outcome. At 6 h post-insult, a stroke volume <0.

Measurement of H2O2 within living Drosophila during aging using a ratiometric mass spectrometry probe targeted to the mitochondrial matrix.

Hydrogen peroxide (H(2)O(2)) is central to mitochondrial oxidative damage and redox signaling, but its roles are poorly understood due to the difficulty of measuring mitochondrial H(2)O(2) in vivo. Here we report a ratiometric mass spectrometry probe approach to assess mitochondrial matrix H(2)O(2) levels in vivo. The probe, MitoB, comprises a triphenylphosphonium (TPP) cation driving its accumulation within mitochondria, conjugated to an arylboronic acid that reacts with H(2)O(2) to form a phenol, MitoP.

Survival in critical illness is associated with early activation of mitochondrial biogenesis.

Rationale: We previously reported outcome-associated decreases in muscle energetic status and mitochondrial dysfunction in septic patients with multiorgan failure. We postulate that survivors have a greater ability to maintain or recover normal mitochondrial functionality.

Objectives: To determine whether mitochondrial biogenesis, the process promoting mitochondrial capacity, is affected in critically ill patients.

Cellular energetic metabolism in sepsis: the need for a systems approach.

Sepsis is a complex pathophysiological disorder arising from a systemic inflammatory response to infection. Patients are clinically classified according to the presence of signs of inflammation alone, multiple organ failure (MOF), or organ failure plus hypotension (septic shock). The organ damage that occurs in MOF is not a direct effect of the pathogen itself, but rather of the dysregulated inflammatory response of the patient.

Compelling EPR evidence that the alternative oxidase is a diiron carboxylate protein.

The alternative oxidase is a respiratory chain protein found in plants, fungi and some parasites that still remains physically uncharacterised. In this report we present EPR evidence from parallel mode experiments which reveal signals at approximately g=16 in both purified alternative oxidase protein (g=16.9), isolated mitochondrial membranes (g=16.

Constitutive activity of Sauromatum guttatum alternative oxidase in Schizosaccharomyces pombe implicates residues in addition to conserved cysteines in alpha-keto acid activation.

Activity of the plant mitochondrial alternative oxidase (AOX) can be regulated by organic acids, notably pyruvate. To date, only two well-conserved cysteine residues have been implicated in this process. We report the functional expression of two AOX isozymes (Sauromatum guttatum Sg-AOX and Arabidopsis thaliana At-AOX1a) in Schizosaccharomyces pombe.