Muscle‐specific sirtuin 3 overexpression does not attenuate the pathological effects of high‐fat/high‐sucrose feeding but does enhance cardiac SERCA2a activity

Oldfield, Christopher J.; Moffatt, Teri L.; O’Hara, Kimberley A.; Xiang, Bo; Dolinsky, Vernon W.; Duhamel, Todd A.

doi:10.14814/phy2.14961

Cited by 5 publications

(6 citation statements)

References 62 publications

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“…This possibility should be experimentally examined by assessing the contractile properties of skeletal muscle from SIRT3 TG mice. SIRT enzymes have been previously reported to modulate cardiac SERCA2a function (Gorski et al 2019;Oldfield et al 2021;Sulaiman et al 2010), with the overexpression of SIRT1 (Gorski et al 2019) and SIRT3 (Oldfield et al 2021) both leading to enhanced maximal SERCA activity in the heart. Our study, however, is the first to examine the modulation of the SERCA pump by SIRT D r a f t proteins in skeletal muscle and the results further establish that SIRTs are positive regulators of SERCA activity.…”

Section: Discussionmentioning

confidence: 99%

“…The mitochondrial fraction was isolated from the gastrocnemius muscle of two mice per group using the Mitochondrial Isolation Kit for Tissue (Fisher Scientific, MA, USA), according to the manufacturer's protocol and as previously described (Oldfield et al 2021)…”

Section: Mitochondrial Fractionationmentioning

confidence: 99%

“…The Signal-Seeker™ Acetyl-Lysine detection kit (Cytoskeleton, CO, USA) was used to measure SERCA1a acetylation and SERCA2a acetylation in gastrocnemius muscle, according to the manufacturer's protocol and as previously described (Oldfield et al 2021). Gastrocnemius muscle tissue was removed from -80°C and immediately lysed with ice-cold BlastR™ lysis buffer (Cytoskeleton, CO, USA) and DNA was removed from the lysate using the BlastR™ filter system (Cytoskeleton, CO, USA).…”

Section: Co-immunoprecipitationmentioning

confidence: 99%

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Sirtuin 3 overexpression preserves maximal sarco(endo)plasmic reticulum calcium ATPase activity in the skeletal muscle of mice subjected to high fat – high sucrose feeding

Oldfield

Moffatt

Dolinsky

et al. 2022

Can. J. Physiol. Pharmacol.

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Sarco(endo)plasmic reticulum calcium (Ca2+) ATPase (SERCA) transports Ca2+ in muscle. Impaired SERCA activity contributes to diabetic myopathy. Sirtuin (SIRT) 3 regulates muscle metabolism and function. However, it is unknown if SIRT3 regulates muscle SERCA activity. We determined if SIRT3 overexpression enhances SERCA activity in mouse gastrocnemius muscle and if SIRT3 overexpression preserves gastrocnemius SERCA activity in a model of type 2 diabetes, induced by high fat-high sucrose (HFHS)-feeding. We also determined if the acetylation status of SERCA proteins in mouse gastrocnemius is altered by SIRT3 overexpression or HFHS-feeding. Wild-type (WT) mice and SIRT3 transgenic (SIRT3TG) mice, overexpressing SIRT3 in skeletal muscle, were fed a standard- or HFHS-diet for 4-months. SIRT3TG and WT mice developed obesity and glucose intolerance after 4-months of HFHS-feeding. SERCA Vmax was higher in gastrocnemius of SIRT3TG mice, compared to WT mice. HFHS-fed mice had lower SERCA1a protein levels and lower SERCA Vmax in their gastrocnemius than control-fed mice. The decrease in SERCA Vmax in gastrocnemius muscle due to HFHS-feeding was attenuated by SIRT3 overexpression in HFHS-fed SIRT3TG mice. SERCA1a and SERCA2a acetylation in mouse gastrocnemius was not altered by genotype or diet. These findings suggest SIRT3 overexpression improves SERCA function in diabetic mouse skeletal muscle.

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Section: Discussionmentioning

confidence: 99%

Section: Mitochondrial Fractionationmentioning

confidence: 99%

Section: Co-immunoprecipitationmentioning

confidence: 99%

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Sirtuin 3 overexpression preserves maximal sarco(endo)plasmic reticulum calcium ATPase activity in the skeletal muscle of mice subjected to high fat – high sucrose feeding

Oldfield

Moffatt

Dolinsky

et al. 2022

Can. J. Physiol. Pharmacol.

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“…In addition, CXCR4 activation promotes NCX1 expression through an NF-κB-dependent pathway in cardiomyocytes in an Akitains 2 model of DCM, and this protects against systolic failure ( 182 ). Furthermore, muscle-specific SIRT3 overexpression seems to increase cardiac activation of SERCA2a in the mouse heart without deacetylating SERCA2a ( 187 ). Another study showed that the acetylation at K492, is important for SERCA2a activity ( 188 ).…”

Section: Pathways Regulating Ca 2+ -Dependent Cont...mentioning

confidence: 99%

Signaling Pathways Related to Oxidative Stress in Diabetic Cardiomyopathy

Peng

et al. 2022

Front. Endocrinol.

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Diabetes is a chronic metabolic disease that is increasing in prevalence and causes many complications. Diabetic cardiomyopathy (DCM) is a complication of diabetes that is associated with high mortality, but it is not well defined. Nevertheless, it is generally accepted that DCM refers to a clinical disease that occurs in patients with diabetes and involves ventricular dysfunction, in the absence of other cardiovascular diseases, such as coronary atherosclerotic heart disease, hypertension, or valvular heart disease. However, it is currently uncertain whether the pathogenesis of DCM is directly attributable to metabolic dysfunction or secondary to diabetic microangiopathy. Oxidative stress (OS) is considered to be a key component of its pathogenesis. The production of reactive oxygen species (ROS) in cardiomyocytes is a vicious circle, resulting in further production of ROS, mitochondrial DNA damage, lipid peroxidation, and the post-translational modification of proteins, as well as inflammation, cardiac hypertrophy and fibrosis, ultimately leading to cell death and cardiac dysfunction. ROS have been shown to affect various signaling pathways involved in the development of DCM. For instance, OS causes metabolic disorders by affecting the regulation of PPARα, AMPK/mTOR, and SIRT3/FOXO3a. Furthermore, OS participates in inflammation mediated by the NF-κB pathway, NLRP3 inflammasome, and the TLR4 pathway. OS also promotes TGF-β-, Rho-ROCK-, and Notch-mediated cardiac remodeling, and is involved in the regulation of calcium homeostasis, which impairs ATP production and causes ROS overproduction. In this review, we summarize the signaling pathways that link OS to DCM, with the intention of identifying appropriate targets and new antioxidant therapies for DCM.

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“…Serotonin is one of the main neurotransmitters that performs a wide range of functions in the body due to the wide variety of receptors from 5-HT1 to 5-HT7, which are both ionotropic (5-HT3) and metabotropic (5-HT2, 5-HT4) [18,19]. The presence of a large number of serotonin receptors in the cardiovascular system [20][21][22] determines the important role of serotonin in the pathogenesis of various cardiovascular diseases (CVDs) [23]. By acting on the walls of blood vessels, 5-HT promotes thrombosis, mitogenesis, proliferation of vascular smooth muscle cells (VSMCs), and the formation of macrophage foam cells [24,25].…”

Section: Introductionmentioning

confidence: 99%

Membrane Transporter of Serotonin and Hypercholesterolemia in Children

Sadykova,

Nigmatullina,

Salakhova

et al. 2024

IJMS

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The serotonin membrane transporter is one of the main mechanisms of plasma serotonin concentration regulation. Serotonin plays an important role in the pathogenesis of various cardiovascular diseases, stimulating the proliferation of smooth muscle cells, key cells in the process of hypertrophic vascular remodeling. Vascular remodeling is one of the leading prognostically unfavorable factors of atherosclerosis, the main manifestation of familial hypercholesterolemia. Familial hypercholesterolemia is one of the most common genetically determined lipid metabolism disorders and occurs in 1 in 313 people. The aim of our study was to investigate the levels of plasma and platelet serotonin, 5-hydroxyindoleacetic acid, and membrane transporter in a cross-sectional study of two pediatric groups, including patients with familial hypercholesterolemia and the control group, which consisted of apparently healthy children without cardiovascular diseases. The study involved 116 children aged 5 to 17 years old. The proportion of boys was 50% (58/116) and the average age of the children was 10.5 years (CI 2.8–18.1). The concentrations of serotonin in blood plasma and platelets and 5-hydroxyindoleacetic acid were higher in children with familial hypercholesterolemia than in the controls. The concentration of the serotonin transporter in platelets in healthy children, compared with the main group, was 1.3 times higher. A positive correlation was revealed between the level of serotonin (5-HT and PWV: ρ = 0.6, p < 0.001), its transporter (SERT and PWV: ρ = 0.5, p < 0.001), and the main indicators of arterial vascular stiffness. Our study revealed the relationship between high serotonin and SERT concentrations and markers of arterial stiffness. The results we obtained suggest the involvement of serotonin and SERT in the process of vascular remodeling in familial hypercholesterolemia in children.

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Muscle‐specific sirtuin 3 overexpression does not attenuate the pathological effects of high‐fat/high‐sucrose feeding but does enhance cardiac SERCA2a activity

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 5 publications

References 62 publications

Sirtuin 3 overexpression preserves maximal sarco(endo)plasmic reticulum calcium ATPase activity in the skeletal muscle of mice subjected to high fat – high sucrose feeding

Sirtuin 3 overexpression preserves maximal sarco(endo)plasmic reticulum calcium ATPase activity in the skeletal muscle of mice subjected to high fat – high sucrose feeding

Signaling Pathways Related to Oxidative Stress in Diabetic Cardiomyopathy

Membrane Transporter of Serotonin and Hypercholesterolemia in Children

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