OPA1 deficiency promotes secretion of FGF21 from muscle that prevents obesity and insulin resistance.

Mitochondrial dynamics is a conserved process by which mitochondria undergo repeated cycles of fusion and fission, leading to exchange of mitochondrial genetic content, ions, metabolites, and proteins. Here, we examine the role of the mitochondrial fusion protein optic atrophy 1 (OPA1) in differentiated skeletal muscle by reducing OPA1 gene expression in an inducible manner. OPA1 deficiency in young mice results in non-lethal progressive mitochondrial dysfunction and loss of muscle mass. Mutant mice are resistant to age- and diet-induced weight gain and insulin resistance, by mechanisms that involve activation of ER stress and secretion of fibroblast growth factor 21 (FGF21) from skeletal muscle, resulting in increased metabolic rates and improved whole-body insulin sensitivity. OPA1-elicited mitochondrial dysfunction activates an integrated stress response that locally induces muscle atrophy, but via secretion of FGF21 acts distally to modulate whole-body metabolism.

Glucose Transporter 3 Potentiates Degranulation and Is Required for Platelet Activation.

OBJECTIVE: On activation, platelets increase glucose uptake, glycolysis, and glucose oxidation and consume stored glycogen. This correlation between glucose metabolism and platelet function is not well understood and even less is known about the role of glucose metabolism on platelet function in vivo. For glucose to enter a cell, it must be transported through glucose transporters. Here we evaluate the contribution of GLUT3 (glucose transporter 3) to platelet function to better understand glucose metabolism in platelets. APPROACH AND RESULTS: Platelet-specific knockout of GLUT3 was generated by crossing mice harboring GLUT3 floxed allele to a PF4 (platelet factor 4)-driven Cre recombinase. In platelets, GLUT3 is localized primarily on α-granule membranes and under basal conditions facilitates glucose uptake into α-granules to be used for glycolysis. After activation, platelets degranulate and GLUT3 translocates to the plasma membrane, which is responsible for activation-mediated increased glucose uptake. In vivo, loss of GLUT3 in platelets increased survival in a collagen/epinephrine model of pulmonary embolism, and in a K/BxN model of autoimmune inflammatory disease, platelet-specific GLUT3 knockout mice display decreased disease progression. Mechanistically, loss of GLUT3 decreased platelet degranulation, spreading, and clot retraction. Decreased α-granule degranulation is due in part to an impaired ability of GLUT3 to potentiate exocytosis. CONCLUSIONS: GLUT3-mediated glucose utilization and glycogenolysis in platelets promotes α-granule release, platelet activation, and postactivation functions.

Assessing effective mask use by the public in two countries: an observational study.

OBJECTIVES: During the COVID-19 pandemic wearing a mask in public has been recommended in some settings and mandated in others. How often this advice is followed, how well, and whether it inadvertently leads to more disease transmission opportunities due to a combination of improper use and physical distancing lapses is unknown. DESIGN: Cross-sectional observational study performed in June-August 2020. SETTING: Eleven outdoor and indoor public settings (some with mandated mask use, some without) each in Toronto, Ontario, and in Portland, Oregon. PARTICIPANTS: All passers-by in the study settings. OUTCOME MEASURES: Mask use, incorrect mask use, and number of breaches (ie, coming within 2 m of someone else where both parties were not properly masked). RESULTS: We observed 36 808 persons, the majority of whom were estimated to be aged 31-65 years (49%). Two-thirds (66.7%) were wearing a mask and 13.6% of mask-wearers wore them incorrectly. Mandatory mask-use settings were overwhelmingly associated with mask use (adjusted OR 79.2; 95% CI 47.4 to 135.1). Younger age, male sex, Torontonians, and public transit or airport settings (vs in a store) were associated with lower adjusted odds of wearing a mask. Mandatory mask-use settings were associated with lower adjusted odds of mask error (OR 0.30; 95% CI 0.14 to 0.73), along with female sex and Portland subjects. Subjects aged 81+ years (vs 31-65 years) and those on public transit and at the airport (vs stores) had higher odds of mask errors. Mask-wearers had a large reduction in adjusted mean number of breaches (rate ratio (RR) 0.19; 95% CI 0.17 to 0.20). The 81+ age group had the largest association with breaches (RR 7.77; 95% CI 5.32 to 11.34). CONCLUSIONS: Mandatory mask use was associated with a large increase in mask-wearing. Despite 14% of them wearing their masks incorrectly, mask users had a large reduction in the mean number of breaches (disease transmission opportunities). The elderly and transit users may warrant public health interventions aimed at improving mask use.

Mitochondrial pyruvate carriers are required for myocardial stress adaptation.

In addition to fatty acids, glucose and lactate are important myocardial substrates under physiologic and stress conditions. They are metabolized to pyruvate, which enters mitochondria via the mitochondrial pyruvate carrier (MPC) for citric acid cycle metabolism. In the present study, we show that MPC-mediated mitochondrial pyruvate utilization is essential for the partitioning of glucose-derived cytosolic metabolic intermediates, which modulate myocardial stress adaptation. Mice with cardiomyocyte-restricted deletion of subunit 1 of MPC (cMPC1-/-) developed age-dependent pathologic cardiac hypertrophy, transitioning to a dilated cardiomyopathy and premature death. Hypertrophied hearts accumulated lactate, pyruvate and glycogen, and displayed increased protein O-linked N-acetylglucosamine, which was prevented by increasing availability of non-glucose substrates in vivo by a ketogenic diet (KD) or a high-fat diet, which reversed the structural, metabolic and functional remodelling of non-stressed cMPC1-/- hearts. Although concurrent short-term KDs did not rescue cMPC1-/- hearts from rapid decompensation and early mortality after pressure overload, 3 weeks of a KD before transverse aortic constriction was sufficient to rescue this phenotype. Together, our results highlight the centrality of pyruvate metabolism to myocardial metabolism and function.

Deletion of GLUT1 and GLUT3 Reveals Multiple Roles for Glucose Metabolism in Platelet and Megakaryocyte Function.

Anucleate platelets circulate in the blood to facilitate thrombosis and diverse immune functions. Platelet activation leading to clot formation correlates with increased glycogenolysis, glucose uptake, glucose oxidation, and lactic acid production. Simultaneous deletion of glucose transporter (GLUT) 1 and GLUT3 (double knockout [DKO]) specifically in platelets completely abolished glucose uptake. In DKO platelets, mitochondrial oxidative metabolism of non-glycolytic substrates, such as glutamate, increased. Thrombosis and platelet activation were decreased through impairment at multiple activation nodes, including Ca2+ signaling, degranulation, and integrin activation. DKO mice developed thrombocytopenia, secondary to impaired pro-platelet formation from megakaryocytes, and increased platelet clearance resulting from cytosolic calcium overload and calpain activation. Systemic treatment with oligomycin, inhibiting mitochondrial metabolism, induced rapid clearance of platelets, with circulating counts dropping to zero in DKO mice, but not wild-type mice, demonstrating an essential role for energy metabolism in platelet viability. Thus, substrate metabolism is essential for platelet production, activation, and survival.