Roles of sarcoplasmic reticulum Ca2+ ATPase pump in the impairments of lymphatic contractile activity in a metabolic syndrome rat model

Abstract

the intrinsic lymphatic contractile activity is necessary for proper lymph transport. Mesenteric lymphatic vessels from high-fructose diet-induced metabolic syndrome (MetSyn) rats exhibited impairments in its intrinsic phasic contractile activity; however, the molecular mechanisms responsible for the weaker lymphatic pumping activity in MetSyn conditions are unknown. Several metabolic disease models have shown that dysregulation of sarcoplasmic reticulum ca 2+ Atpase (SeRcA) pump is one of the key determinants of the phenotypes seen in various muscle tissues. Hence, we hypothesized that a decrease in SeRcA pump expression and/or activity in lymphatic muscle influences the diminished lymphatic vessel contractions in MetSyn animals. Results demonstrated that SERCA inhibitor, thapsigargin, significantly reduced lymphatic phasic contractile frequency and amplitude in control vessels, whereas, the reduced MetSyn lymphatic contractile activity was not further diminished by thapsigargin. While SERCA2a expression was significantly decreased in MetSyn lymphatic vessels, myosin light chain 20, MLC 20 phosphorylation was increased in these vessels. Additionally, insulin resistant lymphatic muscle cells exhibited elevated intracellular calcium and decreased SERCA2a expression and activity. The SERCA activator, CDN 1163 partially restored lymphatic contractile activity in MetSyn lymphatic vessel by increasing phasic contractile frequency. Thus, our data provide the first evidence that SERCA2a modulates the lymphatic pumping activity by regulating phasic contractile amplitude and frequency, but not the lymphatic tone. Diminished lymphatic contractile activity in the vessels from the MetSyn animal is associated with the decreased SERCA2a expression and impaired SERCA2 activity in lymphatic muscle.

Lymphatic Collecting Vessel: New Perspectives on Mechanisms of Contractile Regulation and Potential Lymphatic Contractile Pathways to Target in Obesity and Metabolic Diseases

“…While TRPM4 has yet to be identified in LMCs, investigations into IRAG modulating IP3-mediated calcium releases in LMCs is warranted, particularly as it pertains to activation of Ano1 and regulation of lymphatic contraction frequency. Lastly, the SR store refilling by SERCA in LMCs ( Lee et al, 2020 ) and the calcium sources utilized to refill the store remain underappreciated in lymphatic muscle. Questions remain as to whether the components of the store operated calcium entry, Stim and Orai, are expressed and if they are functional as would be expected for calcium homeostatic control with frequent SR calcium release ( Emrich et al, 2021 ).…”

“…We also found that insulin-resistant LMCs showed decreased endoplasmic reticulum calcium content without affecting non-sarcoplasmic reticulum Ca 2+ ATPase (SERCA)-mediated calcium uptake. Inhibition of SERCA by the irreversible SERCA inhibitor, thapsigargin, in lymphatic vessels diminished both phasic contractile frequency and amplitude without affecting the tone ( Lee et al, 2020 ). There are three distinct genes encoding SERCA pumps, SERCA 1, 2, and 3 resulting in more than 10 SERCA isoforms expressed in various muscles and non-muscle cells ( Hovnanian, 2007 ).…”

“…Among SERCA2, SERCA2a is expressed in cardiac and type 1 slow-twitch skeletal muscle, while SERCA2b is predominantly expressed in smooth muscle cells ( Hovnanian, 2007 ; Periasamy and Kalyanasundaram, 2007 ). Lymphatic muscle expresses both SERCA2a and SERCA2b isoforms ( Lee et al, 2020 ), as lymphatic muscle exhibits a unique combination of muscle cell types that express both cardiac and smooth muscle contractile and regulatory proteins ( Muthuchamy et al, 2003 ).…”

“…Metabolic syndrome condition decreased the levels of SERCA2a expression resulting in impaired Ca 2+ regulation ( Lee et al, 2020 ). SERCA2a is the predominant isoform in striated muscle, and the distinct smooth muscle isoform of SERCA2b is associated with phasic contraction in lymphatic vessels rather than lymphatic tone.…”

Partial-Body Cryostimulation Increases Resting Energy Expenditure in Lean and Obese Women

“…VO 2 in the obese group) [40]. Furthermore, the activity of SERCA was shown to be impaired in animal models of obesity and metabolic syndrome [41,42], potentially representing an adjunctive factor accounting for the poorer response to PBC-induced thermogenesis in the group of obese-women. Thereby, dysmetabolism in obesity could possibly affect muscle substrate oxidation [43], de facto preventing a prompt thermogenic response to cold exposure.…”