The Antibiotic Doxycycline Impairs Cardiac Mitochondrial and Contractile Function

Wüst, Rob C I; Coolen, Bram F.; Held, Ntsiki M.; Daal, Mariah R R; Tazehkandi, Vida Alizadeh; Bulte, Luciënne Baks-Te; Wiersma, Marit; Kuster, Diederik W.D.; Brundel, Bianca J. J. M.; Weeghel, Michel van; Strijkers, Gustav J.; Houtkooper, Riekelt H.

doi:10.3390/ijms22084100

Cited by 24 publications

(28 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Ejection fraction did not differ between groups, however CO, ESV, and EDV were smaller for the db/db mice as compared to controls. These results are consistent with observations in HFpEF patients [ 2 , 32 ] and previous work with db/db mice [ 27 ]. EF did significantly increase over time; however this was not group dependent.…”

Section: Discussionsupporting

confidence: 93%

“…More specifically, systolic force peaks were lower for db/db mice, in line with changes in hemodynamic forces that were observed in HFpEF patients [ 22 ]. Overall, these results show an altered temporal behavior of hemodynamic force parameters in db/db mice as compared to controls and provide additional support to the previously observed negative effects of the antibiotic doxycycline on cardiac function in this mouse model of diabetes [ 27 ]. In healthy subjects, the hemodynamic forces are aligned with the long axis of the LV and in the event of heart failure the hemodynamic forces in iLat-aSep direction increase thus the absolute value of the hemodynamic force ratio between iLat-aSep and apical-basal direction is higher for subjects with heart failure [ 23 ].…”

Section: Discussionsupporting

confidence: 83%

“…The db/db mice are a known model for diastolic dysfunction with preserved ejection fraction thus mimicking aspects of human HFpEF [ 26 ]. Recently we observed that administration of doxycycline exacerbates development of diastolic dysfunction in db/db mice accelerating the progression of HFpEF [ 27 ], due to metabolic and mitochondrial dysfunction [ 27 , 28 ]. As such, we deemed that this model provided us with a feasible intervention that accelerated HFpEF disease progression, better than for instance a myocardial infarction that leads to obvious, rapid and widespread alterations in the LVEF and hence GLS and/or hemodynamic forces.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Longitudinal CMR assessment of cardiac global longitudinal strain and hemodynamic forces in a mouse model of heart failure

Daal

Strijkers

Hautemann

et al. 2022

Int J Cardiovasc Imaging

Self Cite

View full text Add to dashboard Cite

To longitudinally assess left ventricle (LV) global longitudinal strain (GLS) and hemodynamic forces during the early stages of cardiac dysfunction in a mouse model of heart failure with preserved ejection fraction (HFpEF). Cardiac MRI measurements were performed in control mice (n = 6), and db/db mice (n = 7), whereby animals were scanned four times between the age of 11–15 weeks. After the first scan, the db/db animals received a doxycycline intervention to accelerate progression of HFpEF. Systolic function was evaluated based on a series of prospectively ECG-triggered short-axis CINE images acquired from base to apex. Cardiac GLS and hemodynamic forces values were evaluated based on high frame rate retrospectively gated 2-, 3-, and 4-chamber long-axis CINE images. Ejection fraction (EF) was not different between control and db/db animals, despite that cardiac output, as well as end systolic and end diastolic volume were significantly higher in control animals. Whereas GLS parameters were not significantly different between groups, hemodynamic force root mean square (RMS) values, as well as average hemodynamic forces and the ratio between hemodynamic forces in the inferolateral-anteroseptal and apical–basal direction were lower in db/db mice compared to controls. More importantly, hemodynamic forces parameters showed a significant interaction effect between time and group. Our results indicated that hemodynamic forces parameters were the only functional outcome measure that showed distinct temporal differences between groups. As such, changes in hemodynamic forces reflect early alterations in cardiac function which can be of added value in (pre)clinical research on HFpEF.

show abstract

Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Longitudinal CMR assessment of cardiac global longitudinal strain and hemodynamic forces in a mouse model of heart failure

Daal

Strijkers

Hautemann

et al. 2022

Int J Cardiovasc Imaging

Self Cite

View full text Add to dashboard Cite

show abstract

“…To assess mitochondrial morphology by live‐cell imaging, C2C12 myoblasts were processed as described before 21 . 10 × 10 3 myoblasts were seeded on matrigel‐coated 8‐well Ibidi plates and differentiated into myotubes as described above.…”

Section: Methodsmentioning

confidence: 99%

The NLRP3 inflammasome contributes to inflammation‐induced morphological and metabolic alterations in skeletal muscle

Eggelbusch

Shi

Broeksma

et al. 2022

J cachexia sarcopenia muscle

Self Cite

View full text Add to dashboard Cite

Background Systemic inflammation is associated with skeletal muscle atrophy and metabolic dysfunction. Although the nucleotide‐binding oligomerization domain‐like receptor family pyrin domain containing 3 (NLRP3) inflammasome contributes to cytokine production in immune cells, its role in skeletal muscle is poorly understood. Here, we studied the link between inflammation, NLRP3, muscle morphology, and metabolism in in vitro cultured C2C12 myotubes, independent of immune cell involvement. Methods Differentiated C2C12 myotubes were treated with lipopolysaccharide (LPS; 0, 10, and 100–200 ng/mL) to induce activation of the NLRP3 inflammasome with and without MCC950, a pharmacological inhibitor of NLRP3‐induced IL‐1β production. We assessed markers of the NLRP3 inflammasome, cell diameter, reactive oxygen species, and mitochondrial function. Results NLRP3 gene expression and protein concentrations increased in a time‐dependent and dose‐dependent manner. Intracellular IL‐1β concentration significantly increased (P < 0.0001), but significantly less with MCC950 (P = 0.03), suggestive of moderate activation of the NLRP3 inflammasome in cultured myotubes upon LPS stimulation. LPS suppressed myotube growth after 24 h (P = 0.03), and myotubes remained smaller up to 72 h (P = 0.0009). Exposure of myotubes to IL‐1β caused similar alterations in cell morphology, and MCC950 mitigated these LPS‐induced differences in cell diameter. NLRP3 appeared to co‐localize with mitochondria, more so upon exposure to LPS. Mitochondrial reactive oxygen species were higher after LPS (P = 0.03), but not after addition of MCC950. Myotubes had higher glycolytic rates, and mitochondria were more fragmented upon LPS exposure, which was not altered by MCC950 supplementation. Conclusions LPS‐induced activation of the NLRP3 inflammasome in cultured myotubes contributes to morphological and metabolic alterations, likely due to its mitochondrial association.

show abstract

“…Cardiac tissue requires a persistent production of energy in order to exert its pumping function [5,6]. Therefore, maintenance of this function relies on mitochondria that represent the "powerhouse" of all cardiac activities [7].…”

Section: Introductionmentioning

confidence: 99%

Screening for Mitochondrial tRNA Mutations in 318 Patients with Dilated Cardiomyopathy

Qi¹,

Wu²,

Bai³

et al. 2022

Hum Hered

View full text Add to dashboard Cite

Objectives: Dilated cardiomyopathy (DCM) is a complex cardiovascular disease with unknown etiology. Although nuclear genes play active roles in DCM, mitochondrial dysfunction was believed to be involved in the pathogenesis of DCM. The objective of this study is to analysis the association between mitochondrial tRNA (mt-tRNA) mutations and DCM. Material and Methods: We performed a mutational analysis of mt-tRNA genes in a cohort of 318 patients with DCM and 200 age- and gender-matched control subjects. To further assess their pathogenicity, phylogenetic analysis and mitochondrial functions including mtDNA copy number, ATP and ROS were analyzed. Results: 7 possible pathogenic mutations: MT-TL1 3302A>G, MT-TI 4295A>G, MT-TM 4435A>G, MT-TA 5655T>C, MT-TH 12201T>C, MT-TE 14692A>G and MT-TT 15927G>A were identified in DCM group but absent in controls. These mutations occurred at extremely conserved nucleotides of corresponding tRNAs, and led to the failure in tRNAs metabolism. Moreover, a significant reduction in ATP and mtDNA copy number, whereas a markedly increased in ROS level were observed in polymononuclear leukocytes (PMNs) derived from the DCM patients carrying these mt-tRNA mutations, suggesting that these mutations may cause mitochondrial dysfunction that was responsible for DCM. Conclusions: Our data indicated that mt-tRNA mutations may be the molecular basis for DCM, which shaded novel insight into the pathophysiology of DCM that was manifestated by mitochondrial dysfunction.

show abstract

The Antibiotic Doxycycline Impairs Cardiac Mitochondrial and Contractile Function

Cited by 24 publications

References 59 publications

Longitudinal CMR assessment of cardiac global longitudinal strain and hemodynamic forces in a mouse model of heart failure

Longitudinal CMR assessment of cardiac global longitudinal strain and hemodynamic forces in a mouse model of heart failure

The NLRP3 inflammasome contributes to inflammation‐induced morphological and metabolic alterations in skeletal muscle

Screening for Mitochondrial tRNA Mutations in 318 Patients with Dilated Cardiomyopathy

Contact Info

Product

Resources

About