Adaptive thermogenesis enhances the life-threatening response to heat in mice with an Ryr1 mutation

doi:10.1038/s41467-020-18865-z

. 2020 Oct 9;11(1):5099.

doi: 10.1038/s41467-020-18865-z.

Adaptive thermogenesis enhances the life-threatening response to heat in mice with an Ryr1 mutation

Hui J Wang^#^{1

2}, Chang Seok Lee^#¹, Rachel Sue Zhen Yee¹, Linda Groom³, Inbar Friedman⁴, Lyle Babcock¹, Dimitra K Georgiou¹, Jin Hong¹, Amy D Hanna¹, Joseph Recio¹, Jong Min Choi⁵, Ting Chang¹, Nadia H Agha¹, Jonathan Romero¹, Poonam Sarkar⁶, Nicol Voermans⁷, M Waleed Gaber^{1

6}, Sung Yun Jung⁵, Matthew L Baker⁵, Robia G Pautler¹, Robert T Dirksen³, Sheila Riazi⁴, Susan L Hamilton⁸

Affiliations

¹ Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.
² Translational Biology and Molecular Medicine Graduate Program, Baylor College of Medicine, Houston, TX, USA.
³ Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, USA.
⁴ Department of Anesthesiology, University of Toronto, Toronto, ON, Canada.
⁵ Advance Technology Core, Mass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, TX, USA.
⁶ Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
⁷ Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Nijmegen, Netherlands.
⁸ Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA. susanh@bcm.edu.

^# Contributed equally.

PMID: 33037202
PMCID: PMC7547078
DOI: 10.1038/s41467-020-18865-z

Adaptive thermogenesis enhances the life-threatening response to heat in mice with an Ryr1 mutation

Hui J Wang et al. Nat Commun. 2020.

. 2020 Oct 9;11(1):5099.

doi: 10.1038/s41467-020-18865-z.

Authors

Affiliations

¹ Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.
² Translational Biology and Molecular Medicine Graduate Program, Baylor College of Medicine, Houston, TX, USA.
³ Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, USA.
⁴ Department of Anesthesiology, University of Toronto, Toronto, ON, Canada.
⁵ Advance Technology Core, Mass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, TX, USA.
⁶ Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
⁷ Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Nijmegen, Netherlands.
⁸ Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA. susanh@bcm.edu.

^# Contributed equally.

PMID: 33037202
PMCID: PMC7547078
DOI: 10.1038/s41467-020-18865-z

Abstract

Mutations in the skeletal muscle Ca²⁺ release channel, the type 1 ryanodine receptor (RYR1), cause malignant hyperthermia susceptibility (MHS) and a life-threatening sensitivity to heat, which is most severe in children. Mice with an MHS-associated mutation in Ryr1 (Y524S, YS) display lethal muscle contractures in response to heat. Here we show that the heat response in the YS mice is exacerbated by brown fat adaptive thermogenesis. In addition, the YS mice have more brown adipose tissue thermogenic capacity than their littermate controls. Blood lactate levels are elevated in both heat-sensitive MHS patients with RYR1 mutations and YS mice due to Ca²⁺ driven increases in muscle metabolism. Lactate increases brown adipogenesis in both mouse and human brown preadipocytes. This study suggests that simple lifestyle modifications such as avoiding extreme temperatures and maintaining thermoneutrality could decrease the risk of life-threatening responses to heat and exercise in individuals with RYR1 pathogenic variants.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1. Heat intolerance in patients and mice with *RYR1* pathogenic variants associated with malignant hyperthermia susceptibility (MHS).**
a Survival rate of heat intolerant patients carrying *RYR1* variants associated with MHS among age groups. b Symptoms associated with heat intolerance in male and female carriers. c Proportion of symptomatic carriers with heat-intolerant symptoms in male and female carriers. d Pathogenicity of *RYR1* variants associated with heat-sensitivity. e Kaplan–Meier analysis of the survival rate of WT (n = 50, male and n = 12, female) and YS (n = 70, male and n = 18, female) mice after acute heat challenge. f Relationship of the age of mice and maxVO₂ during acute heat challenge in WT (n = 125) and YS (n = 151) mice. g Effect of age on the estimated survival probability of YS mice (n = 159) after acute heat challenge. h Kaplan–Meier analysis of the heat challenge survival rate of YS mice (n = 124) grouped by age. All mice were housed at room ambient temperature (20.2 ± 0.4 °C) prior to heat challenge. All mice were within the controlled age range (8.9 ± 0.9 week old) at the time of the study, except for the age-dependent experiments (f–h). P values are indicated as analyzed by Fisher’s exact test (a, c), Mantel–Cox log-rank test (e, h), and F-test for deviation from zero-slope of linear regression (f). All statistical tests are two-sided. R² values are indicated to quantify goodness-of-fit to non-linear regression with variable slope (g). Data are represented as mean ± 95% confidence intervals (CI) from the linear best-fit line (f). Survival probability of each muse is estimated based on the survival rate from ten mice in the respective age subgroups (g). Effect of age of the YS mice on survival of the heat challenge was determined by assessing survival probability as a function of age. The EA₅₀ is defined as the half-maximal effective age (g). The effect of age on survival of individuals (panel a) with *RYR1* mutations was also assessed. The pediatric subgroup is defined as 17 years of age and younger, and the adult subgroup is defined as 18 years of age and older. Sample sizes, odds ratios, and 95% confidence intervals (CI) are indicated. Source data are provided as a source data file.

**Fig. 2. Enhanced heat sensitivity and elevated core body temperature in Y524S mice.**
a Maximum oxygen consumption rate (maxVO₂) of WT (n = 92) and YS (n = 115) mice during heat challenge at the indicated temperatures. b Distribution of baseline core body temperature of WT (n = 175) and YS (n = 202) mice at room temperature. c, d Comparison of baseline core body temperatures of WT and YS mice in littermate pairs analyzed per litter (c n = 56 pairs) and per individual animals (d n = 177 pairs). e Relationship of baseline core body temperature and hyperthermia response after acute 37 °C heat challenge in WT (n = 66) and YS (n = 85) mice. f Effect of baseline core body temperature on the estimated survival probability of YS mice (n = 85) after acute heat challenge. g Kaplan–Meier analysis of the heat challenge survival rate of YS mice (n = 85) grouped by baseline core body temperature. All mice were housed at room ambient temperature (20.2 ± 0.4 °C) prior to heat challenge. All mice were within the controlled age range (8.9 ± 0.9 week old) at the time of study. P values are indicated as analyzed by F-test for differential slope of linear regressions (a), paired t test (c, d), F-test for deviation from zero-slope of linear regression (e, f), and Mantel–Cox log-rank test (g). All statistical tests are two-sided. R² values are indicated to quantify goodness-of-fit to Gaussian distribution (b). Survival probability of each mouse is estimated based on the survival rate from ten mice in the respective core body temperature (f) subgroups. Data are represented as asymmetrical 95% confidence intervals (CI) from linear best-fit line (a, e). Source data are provided as a source data file.

**Fig. 3. Enhanced heat sensitivity and adaptive thermogenesis in Y524S mice.**
a Relationship of ambient housing temperature and the maxVO₂ during acute 37 °C heat challenge in WT (n = 129) and YS (n = 154) mice. b Effect of prior median ambient housing temperature on estimated survival probability of YS mice (n = 154) after acute heat challenge. c Kaplan–Meier analysis of the heat challenge survival rate of YS mice (n = 154) grouped by duration of prior ambient housing temperature at lower than 20 °C. d, e Core body temperature before (d) and after (e) acute 37 °C heat challenge in WT and YS mice preconditioned for 1 week at 4 °C (WT n = 23, YS n = 21), room temperature (WT n = 35, YS n = 40), and 30 °C (WT n = 6, YS n = 11) ambient environment. f, g Core body temperature before (f) and after (g) acute 37 °C heat challenge in YS mice preconditioned at fasted (n = 6) and refed state (n = 11, post-heat challenge temperature of one refed YS mice was not measured due to full body contracture). All mice were within the controlled age range (8.9 ± 0.9 week old) at the time of study. P values are indicated as analyzed by F-test for deviation from zero-slope of linear regression (a), Mantel–Cox log-rank test (c), ordinary one-way analysis of variance (ANOVA) with Dunnett’s multiple comparisons test (d, e) and Welch’s t test (f, g). All statistical tests are two-sided. R² values are indicated to quantify goodness-of-fit to nonlinear regression with variable slope (b). Survival probability of each mouse is estimated based on the survival rate from ten mice in the respective ambient temperature (b) subgroups. Effect of ambient housing temperature on heat challenge survival is measured by half-maximal effective ambient housing temperature (ET₅₀) on the estimated survival probability (b). Data are represented as asymmetrical 95% confidence intervals (CI) from linear best-fit line (a), or mean ± standard deviation (d–g). Source data are provided as a source data file.

**Fig. 4. Pharmacological and genetic modulation of adipose tissue thermogenic activity alters heat sensitivity of Y524S mice.**
a, b MaxVO₂ (a) and maxVCO₂ (b) of WT (n = 108) and YS (n = 146) mice with or without heterozygous genetic ablation of the mitochondrial uncoupling protein (Ucp1^WT/null) during acute heat challenge at 37 °C. c Kaplan–Meier analysis of the survival rate of WT (n = 108) and YS mice (n = 146) with or without *Ucp1*-ablation (heterozygous) after acute heat challenge. d, e Maximal O₂ consumption (maxVO₂, d) and CO₂ production (maxVCO₂, e) rate of WT (n = 53) and YS (n = 108) mice pretreated with β3-adrenergic receptor (β₃AR) antagonist (L748337, 1 mg/kg) or vehicle control during acute heat challenge at 37 °C. f Kaplan–Meier analysis of the survival rate of WT (n = 53) and YS mice (n = 108) pretreated with β₃AR antagonist or vehicle control after acute heat challenge. g, h Heat sensitivity of WT mice (n = 76, g) and YS mice (n = 106, h) pretreated with β₃AR agonist (BRL37344, 1 mg/kg) or vehicle control as measured by half-maximal effective temperature (ET₅₀) on O₂ consumption rate for mice during acute exposure to various temperatures. i Effect of β₃AR agonist on heat sensitivity of YS mice (n = 106) as measured by ET₅₀ on survival rate of mice after acute exposures. All mice were within the controlled age range (8.8 ± 1.0 week old) at the time of study. P values are indicated as analyzed by ordinary one-way analysis of variance (ANOVA) with Tukey’s multiple comparisons test (a, b, d, e), and Mantel–Cox log-rank test (c, f), and F-test for differential ET₅₀ of nonlinear regression with variable slope (g–i). Effects on heat sensitivity alteration in mice are established by comparing littermates of the same genotype with or without the genetic (a–c) or pharmacological (d–i) interventions. All statistical tests are two-sided. Data are represented as mean ± standard deviation (a, b, d, e), or asymmetrical 95% confidence non-linear best-fit curve (g–i). Source data are provided as a source data file.

**Fig. 5. Elevated brown adipose tissue thermogenic capacity and white adipose tissue browning in Y524S mice.**
a Gross anatomy for the interscapular brown adipose tissue (iBAT) from WT and YS littermates. b, c Tissue to body weight ratio of iBAT resected from littermate pairs of WT and YS in male (n = 42 pairs, b) and female (n = 36 pairs, c) mice. d Representative PET-CT scan of WT and YS littermate. e Quantification of total iBAT activity in WT and YS littermates (n = 16 pairs). f Representative PET-CT scans from the interscapular region of WT and YS mice from various age groups. g–i Age related decline of body weight-adjusted total iBAT activity in WT (n = 28, g) and YS (n = 17, h) mice, and comparison between WT and YS within age groups (i). j Relative UCP1 protein levels in iBAT from WT (n = 10) and YS (n = 10) littermates. k H&E stain images of subcutaneous inguinal white adipose tissue (iWAT) from WT and YS littermate. Morphological changes are consistent across three independent littermate pairs. l Relative protein levels of UCP1 in iWAT from WT (n = 22) and YS (n = 22) littermates, using iBAT as a positive control. P values are indicated as analyzed by paired t test (b, c, e), F-test for deviation from zero-rate constant of nonlinear regression (g, h), and two-way ANOVA with Sidak’s multiple comparisons test (i), and Welch’s t test (j, l). All statistical tests are two-sided. R² values are indicated to quantify goodness-of-fit to nonlinear regression with variable slope (g, h). Data are represented as mean ± standard deviation (i, j, l), or asymmetrical 95% confidence intervals (CI) from nonlinear best-fit curve (g, h). Mice were within the controlled age range (male: 12.0 ± 0.3-week-old (b), and female: 11.9 ± 0.3 week old (c)) at the time of study, except for the age-dependent experiments (g–i). Display ranges of standard uptake value (SUV) for PET and Hounsfield unit (HU) for CT are as indicated (f). Scale bars are 5 mm from the gross anatomy images (a), 10 mm from the PET-CT scans (d, f), and 100 μm from the histological images (k). Source data are provided as a source data file.

**Fig. 6. Increased circulating levels of skeletal muscle-derived lactate in the Y524S mice.**
a Volcano plot comparing the levels of circulating factors in WT (n = 4) and YS (n = 4) littermates. b Blood lactate concentration of WT and YS littermates as measured in filtered serum collected during day (WT n = 12, YS n = 16) and night (WT n = 20, YS n = 20) time. c Relationship of gastrocnemius muscle glycogen and blood lactate levels in WT (n = 18) and YS (n = 15) mice. d, e Muscle glycogen (d) and glucose (e) concentration as measured in gastrocnemius muscle isolated from WT (n = 18) and YS (n = 15) littermates. f Representative ³¹P nuclear magnetic resonance (NMR) spectra of hindlimb muscles measured in vivo from WT and YS littermate. g Quantification of phosphocreatine to inorganic phosphate ratio (PCr/Pi) based on analysis of the ³¹P NMR spectra from WT (n = 8) and YS (n = 8) hindlimb muscles. h–j Volcano plot comparing the level of proteomic changes in soleus (h), EDL (i), and diaphragm (j) muscle of WT (n = 3) and YS (n = 3) littermates. P values are indicated as analyzed by two-side unpaired t test without adjustment for multiple comparisons (a, h–j), ordinary one-way analysis of variance (ANOVA) with Tukey’s multiple comparisons test (b), and Welch’s t test (d, e, g). All statistical tests are two-sided. R² values are indicated to quantify goodness-of-fit to nonlinear regression with variable slope (c). Data are represented as mean ± standard deviation (b, d, e, g). Mice were within the controlled age range (10.0 ± 1.8 week old) at the time of study. Source data are provided as a source data file.

**Fig. 7. Lactate promotes brown adipogenesis in brown preadipocytes.**
a, b Representative immunoblots (a) and relative protein levels (b) for mitochondrial uncoupling protein (UCP1) in differentiation assay of interscapular brown adipose tissue (iBAT) stromal–vascular fraction (SVF) cells treated with vehicle control (n = 19), lactate (n = 19), monocarboxylate transporter (MCT1/2) inhibitor (n = 4) or both (n = 4). c, d Representative immunoblots (c) and relative protein levels (d) for UCP1 in mitochondrial fraction of differentiated iBAT SVF cells treated with vehicle (n = 9), lactate (n = 9), MCT1/2 inhibitor (n = 9) or both (n = 8). One data point (Lactate + ARC = 182.6% of control) identified as a statistical outlier (more than 2.04σ above the group mean) was excluded from the analysis based on the Grubb’s method. e, f Representative cell cycle distributions (e) and relative proportions (f) of G1 phase brown-selective preadipocytes in proliferation assay of iBAT SVF cells treated with vehicle (n = 9), lactate (n = 9), MCT1/2 inhibitor (n = 3) or both (n = 3). g Representative contour plots of platelet-derived growth factor receptor α-positive (PDGFRα⁺) preadipocytes in primary iBAT SVF cells isolated from P2.5 neonates of WT and YS littermate. h, i Relative early B cell factor-2-positive (EBF2⁺) frequency (h) and relative cell size (forward scatter, i) in PDGFRα⁺ preadipocytes in primary iBAT SVF cells from P2.5 neonates of WT (n = 7) and YS (n = 9) littermates. P values are indicated as analyzed by ordinary one-way analysis of variance (ANOVA) with Dunnett’s multiple comparisons test (b, d, f), and Welch’s t test (h, i). All statistical tests are two-sided. Data are represented as mean ± standard deviation. Relative protein levels are determined as protein levels normalized to vehicle (b, d, f) treated controls. Relative proportions are determined as proportions normalized to the level of wild-type littermate controls (h, i). Source data are provided as a source data file.

**Fig. 8. Lactate promotes brown adipogenesis in white preadipocytes.**
a, b Representative immunoblots (a) and relative protein levels (b) for mitochondrial uncoupling protein UCP1 in differentiation assay of inguinal white adipose tissue (iWAT) SVF cells treated with vehicle (n = 21), lactate (n = 21), MCT1/2 inhibitor (n = 6) or both (n = 6). c, d Representative immunoblots (c) and relative protein levels (d) for UCP1 in differentiation assay of 3T3-L1 preadipocytes treated with vehicle (n = 8), lactate (n = 8), MCT1/2 inhibitor (n = 4) or both (n = 6). e, f Representative immunoblots (e) and relative protein levels (f) for UCP1 in differentiation assay of 3T3-L1 preadipocytes treated with unfiltered serum (10%) from WT (n = 11) or YS (n = 11) mice. g, h Representative immunoblots (g) and relative protein levels (h) for UCP1 in differentiation assay 3T3-L1 preadipocytes treated with 10 kb-filtered serum (20%) from WT and YS mice, with (WT, n = 12, YS, n = 11) or without (WT, n = 6, YS, n = 6) the MCT1/2 inhibitor. P values are indicated as analyzed by ordinary one-way analysis of variance (ANOVA) with Dunnett’s multiple comparisons test (b, d, h), Welch’s t test (f). All statistical tests are two-sided. Data are represented as mean ± standard deviation. Relative protein levels are determined as protein levels normalized to vehicle (a, b) or wild-type mouse serum (f, h) treated controls. Source data are provided as a source data file.

**Fig. 9. Increased blood lactate in heat-sensitive MHS patients and its effect on human preadipocyte brown adipogenesis.**
a Blood lactate concentration of non-heat sensitive (n = 5) and heat-sensitive (n = 10) MHS patients carrying RYR1 variants. b, c Representative immunoblots (b) and relative protein levels (c) for the mitochondrial uncoupling protein (UCP1) in differentiation assay of immortalized human preadipocytes from stromal–vascular fraction of brown adipose tissue treated with vehicle control and different dose of ectopic lactate (n = 5 each). d Proposed model of an adaptive thermogenesis enhanced feed-forward cycle of heat-induced heat response in susceptible patients. P values are indicated as Welch’s t test (a, c). All statistical tests are two-sided. Data are represented as mean ± standard deviation (a) and mean ± standard error of the mean (c). Relative protein levels are determined as levels normalized to the level of vehicle-treated controls (c). Source data are provided as a source data file.

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References

1. Monnier N, Procaccio V, Stieglitz P, Lunardi J. Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am. J. Hum. Genet. 1997;60:1316–1325. doi: 10.1086/515454. - DOI - PMC - PubMed
1. Wappler F. Anesthesia for patients with a history of malignant hyperthermia. Curr. Opin. Anaesthesiol. 2010;23:417–422. doi: 10.1097/ACO.0b013e328337ffe0. - DOI - PubMed
1. Monnier N, et al. Presence of two different genetic traits in malignant hyperthermia families: implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility. Anesthesiology. 2002;97:1067–1074. doi: 10.1097/00000542-200211000-00007. - DOI - PubMed
1. Brady JE, Sun LS, Rosenberg H, Li G. Prevalence of malignant hyperthermia due to anesthesia in New York State, 2001-2005. Anesth. Analg. 2009;109:1162–1166. doi: 10.1213/ane.0b013e3181ac1548. - DOI - PubMed
1. Strazis KP, Fox AW. Malignant hyperthermia: a review of published cases. Anesth. Analg. 1993;77:297–304. doi: 10.1213/00000539-199308000-00014. - DOI - PubMed

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[1] Monnier N, Procaccio V, Stieglitz P, Lunardi J. Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am. J. Hum. Genet. 1997;60:1316–1325. doi: 10.1086/515454. - DOI - PMC - PubMed

[2] Monnier N, Procaccio V, Stieglitz P, Lunardi J. Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am. J. Hum. Genet. 1997;60:1316–1325. doi: 10.1086/515454. - DOI - PMC - PubMed

[3] Wappler F. Anesthesia for patients with a history of malignant hyperthermia. Curr. Opin. Anaesthesiol. 2010;23:417–422. doi: 10.1097/ACO.0b013e328337ffe0. - DOI - PubMed

[4] Wappler F. Anesthesia for patients with a history of malignant hyperthermia. Curr. Opin. Anaesthesiol. 2010;23:417–422. doi: 10.1097/ACO.0b013e328337ffe0. - DOI - PubMed

[5] Monnier N, et al. Presence of two different genetic traits in malignant hyperthermia families: implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility. Anesthesiology. 2002;97:1067–1074. doi: 10.1097/00000542-200211000-00007. - DOI - PubMed

[6] Monnier N, et al. Presence of two different genetic traits in malignant hyperthermia families: implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility. Anesthesiology. 2002;97:1067–1074. doi: 10.1097/00000542-200211000-00007. - DOI - PubMed

[7] Brady JE, Sun LS, Rosenberg H, Li G. Prevalence of malignant hyperthermia due to anesthesia in New York State, 2001-2005. Anesth. Analg. 2009;109:1162–1166. doi: 10.1213/ane.0b013e3181ac1548. - DOI - PubMed

[8] Brady JE, Sun LS, Rosenberg H, Li G. Prevalence of malignant hyperthermia due to anesthesia in New York State, 2001-2005. Anesth. Analg. 2009;109:1162–1166. doi: 10.1213/ane.0b013e3181ac1548. - DOI - PubMed

[9] Strazis KP, Fox AW. Malignant hyperthermia: a review of published cases. Anesth. Analg. 1993;77:297–304. doi: 10.1213/00000539-199308000-00014. - DOI - PubMed

[10] Strazis KP, Fox AW. Malignant hyperthermia: a review of published cases. Anesth. Analg. 1993;77:297–304. doi: 10.1213/00000539-199308000-00014. - DOI - PubMed

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Adaptive thermogenesis enhances the life-threatening response to heat in mice with an Ryr1 mutation

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Adaptive thermogenesis enhances the life-threatening response to heat in mice with an Ryr1 mutation

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