Aerobic Training Prevents Heatstrokes in Calsequestrin‐1 Knockout Mice by Reducing Oxidative Stress

Guarnier, Flávia Alessandra; Michelucci, Antonio; Serano, Matteo; Pietrangelo, Laura; Pecorai, Claudia; Boncompagni, Simona; Protasi, Feliciano

doi:10.1155/2018/4652480

Cited by 9 publications

(24 citation statements)

References 85 publications

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“…Similar to STIM1 and Orai1, quantitative analyses revealed a modest (∼25%) but statistically significant increase of SERCA expression in EDL muscle from CASQ1-null mice ( Fig. 4, C and G ), consistent with prior reports of increased SERCA activity in muscle from these mice ( Guarnier et al, 2018 ).…”

Section: Resultssupporting

confidence: 88%

“…Muscle fibers from CASQ1 KO (CASQ1-null) mice exhibit severely reduced releasable SR Ca 2+ store content and enhanced susceptibility to rapid and deep SR Ca 2+ depletion during sustained, high-frequency stimulation ( Paolini et al, 2007 ; Canato et al, 2010 ; Sztretye et al, 2011b ). CASQ1-deficiency also leads to an increased susceptibility of mice to hyperthermic crises during exposure to halogenated anesthetics, heat, and exercise ( Dainese et al, 2009 ; Protasi et al, 2009 ; Michelucci et al, 2015 , 2017 ; Guarnier et al, 2018 ) and mitochondrial alterations that progress to more severe structural damage with age ( Paolini et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

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Pre-assembled Ca2+ entry units and constitutively active Ca2+ entry in skeletal muscle of calsequestrin-1 knockout mice

Michelucci

Boncompagni

Pietrangelo

et al. 2020

Journal of General Physiology

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Store-operated Ca2+ entry (SOCE) is a ubiquitous Ca2+ influx mechanism triggered by depletion of Ca2+ stores from the endoplasmic/sarcoplasmic reticulum (ER/SR). We recently reported that acute exercise in WT mice drives the formation of Ca2+ entry units (CEUs), intracellular junctions that contain STIM1 and Orai1, the two key proteins mediating SOCE. The presence of CEUs correlates with increased constitutive- and store-operated Ca2+ entry, as well as sustained Ca2+ release and force generation during repetitive stimulation. Skeletal muscle from mice lacking calsequestrin-1 (CASQ1-null), the primary Ca2+-binding protein in the lumen of SR terminal cisternae, exhibits significantly reduced total Ca2+ store content and marked SR Ca2+ depletion during high-frequency stimulation. Here, we report that CEUs are constitutively assembled in extensor digitorum longus (EDL) and flexor digitorum brevis (FDB) muscles of sedentary CASQ1-null mice. The higher density of CEUs in EDL (39.6 ± 2.1/100 µm2 versus 2.0 ± 0.3/100 µm2) and FDB (16.7 ± 1.0/100 µm2 versus 2.7 ± 0.5/100 µm2) muscles of CASQ1-null compared with WT mice correlated with enhanced constitutive- and store-operated Ca2+ entry and increased expression of STIM1, Orai1, and SERCA. The higher ability to recover Ca2+ ions via SOCE in CASQ1-null muscle served to promote enhanced maintenance of peak Ca2+ transient amplitude, increased dependence of luminal SR Ca2+ replenishment on BTP-2-sensitive SOCE, and increased maintenance of contractile force during repetitive, high-frequency stimulation. Together, these data suggest that muscles from CASQ1-null mice compensate for the lack of CASQ1 and reduction in total releasable SR Ca2+ content by assembling CEUs to promote constitutive and store-operated Ca2+ entry.

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Section: Resultssupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Pre-assembled Ca2+ entry units and constitutively active Ca2+ entry in skeletal muscle of calsequestrin-1 knockout mice

Michelucci

Boncompagni

Pietrangelo

et al. 2020

Journal of General Physiology

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“…Diet rich in fat may induce oxidative stress, potentially through the up-regulated expression of genes for ROS production and through mitochondrial respiratory chain overload [28]. As we have demonstrated that mice models susceptible to HS crises display high level of oxidative stress [22,23,25,26,29] in the present study, we tested whether high-fat diet administrated to WT mice may predispose to environmental HS crisis.…”

Section: Introductionmentioning

confidence: 90%

“…Correlation between MH and HS (hypothesized in humans) have been already demonstrated in animal models carrying speci c gene mutations: a) swine that carry a point mutation in the skeletal muscle ryanodine receptor type-1 (RyR1) trigger MH episodes in response to halothane administration, but also during exposure to either heat or emotional/physical stress [17,18]; b) knock-in mice that carry gain-offunction mutations in the RYR1 gene that are causative of MHS in humans (R163C and Y522S) are susceptible to lethal overheating crises when exposed to either halogenated anesthetics or elevated temperature [19,20]; nally c) mice that lack the protein calsequestrin-1 (CASQ1-null) also exhibit lethal anesthetic-and heat-induced hyperthermic episodes [21][22][23][24]. Studies from our group and others indicates that rhabdomyolysis of skeletal muscle bers during MHS/HS crisis is the nal result of complex cascade of events starting from excessive Ca 2+ leak from RyR1 mediated by oxidative stress and consequent nitrosylation of RyR1 [25].…”

Section: Introductionmentioning

confidence: 99%

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High-fat diet impairs muscle function and increases the risk of environmental heatstroke in mice

Serano

Paolini

Michelucci

et al. 2022

Preprint

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Background. Environmental heat-stroke (HS) is a life-threatening response often triggered by a hot and humid weather. HS is characterized by an abnormal increase in body temperature (>40°C) causing dysfunction of organs, central nervous system, and that may end in death. Several lines of evidence indicate that environmental HS is caused by excessive heat production in skeletal muscle, which in turn is the result of abnormal Ca2+ leak from the sarcoplasmic reticulum (SR) and excessive production of oxidative species of oxygen and nitrogen (ROS and NOS). Methods. As high fat diet is known to increase oxidative stress, the objective of the present study was to investigate the effects of 3 months of high-fat diet (HFD) on HS susceptibility of wild type (WT) mice. HS susceptibility was tested in an environmental chamber where 4 months old mice (adult) were exposed to heat stress (41°C for 1 hr). Results. In comparison with mice fed with a regular diet, mice subjected to 3 months of HFD showed: a) increased body weight and accumulation of adipose tissue; b) elevated oxidative stress in both EDL and Soleus muscles (assessed by western blot of 3-NT levels and of expression of antioxidant enzymes such as SODs and Catalase) ; c) increased heat generation and oxygen consumption during exposure to environmental heat stress (oxygen consumption was assessed by indirect calorimetry) ; and finally d) enhanced sensitivity to both temperature and caffeine of isolated EDL and Soleus muscles during in vitro contracture test (IVCT), i.e. the gold standard procedure used to verify in-vitro HS susceptibility.Conclusions. The data collected suggest that HFD predisposes WT mice to HS, possibly as a result of elevated myoplasmic Ca2+ (indirectly assessed by IVCT) and increased oxidative stress (directly assessed by WB). These results could in principle have implications for the development of guidelines regarding food intake during periods of intense environmental heat.

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ACSL4 contributes to ferroptosis‐mediated rhabdomyolysis in exertional heat stroke

Peng

et al. 2022

J cachexia sarcopenia muscle

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Background Rhabdomyolysis (RM) is a common complication of exertional heat stroke (EHS) and constitutes a direct cause of death. However, the mechanism underlying RM following EHS remains unclear. Methods The murine EHS model was prepared by our previous protocol. RNA sequencing is applied to identify the pathological pathways that contribute to RM following EHS. Inhibition of the acyl‐CoA synthetase long‐chain family member 4 (ACSL4) was achieved by RNA silencing in vitro prior to ionomycin plus heat stress exposure or pharmacological inhibitors in vivo prior to heat and exertion exposure. The histological changes, the iron accumulation, oxidized phosphatidylethanolamines species, as well as histological evaluation and levels of lipid metabolites in skeletal muscle tissues were measured. Results We demonstrated that ferroptosis contributes to RM development following EHS. Ferroptosis inhibitor ferrostatin‐1 administration once EHS onset significantly ameliorated the survival rate of EHS mice from 35.357% to 52.288% within 24 h after EHS (P = 0.0028 compared with control) and markedly inhibited RM development induced by EHS. By comparing gene expression of between sham heat rest (SHR) (n = 3) and EHS (n = 3) mice in the gastrocnemius (Gas) muscle tissue, we identified that Acsl4 mRNA expression is elevated in Gas muscle tissue of EHS mice (P = 0.0038 compared with SHR), so as to its protein levels (P = 0.0001 compared with SHR). Followed by increase in creatine kinase (CK) and myoglobin (MB) levels, the labile iron accumulation, decrease in glutathione peroxidase 4 (GPX4) expression, and elevation of lipid peroxidation products. From in vivo and in vitro experiments, inhibition of Acsl4 significantly improves muscle cell death caused by EHS, thereby ameliorating RM development, followed by reduction in CK and MB levels by 30–40% (P < 0.0001; n = 8–10) and 40% (P < 0.0001; n = 8–10), restoration of GPX4 expression, and decrease in lipid peroxidation products. Mechanistically, ACSL4‐mediated RM seems to be Yes‐associated protein (YAP) dependent via TEA domain transcription factor1/TEA domain transcription factor4. Conclusions These findings demonstrate an important role of ACSL4 in mediating ferroptosis activation in the development of RM following EHS and suggest that targeting ACSL4 may represent a novel therapeutic strategy to limit the skeletal muscle cell death and prevent RM after EHS.

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Aerobic Training Prevents Heatstrokes in Calsequestrin‐1 Knockout Mice by Reducing Oxidative Stress

Cited by 9 publications

References 85 publications

Pre-assembled Ca2+ entry units and constitutively active Ca2+ entry in skeletal muscle of calsequestrin-1 knockout mice

Pre-assembled Ca2+ entry units and constitutively active Ca2+ entry in skeletal muscle of calsequestrin-1 knockout mice

High-fat diet impairs muscle function and increases the risk of environmental heatstroke in mice

ACSL4 contributes to ferroptosis‐mediated rhabdomyolysis in exertional heat stroke

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