The Molecular Mechanisms and Clinical Implications of Skeletal Muscle Calcium Release Channel Mediated Systemic Thermoregulation Associated with Malignant Hyperthermia
Heatstroke is a life-threatening condition characterized by severe hyperthermia and multiorgan-dysfunction resulting from exposure to heat. While it often occurs under prolonged exposure to extreme environmental or exertional heat, which is preventable in most individuals, patients with certain genetic predispositions are particularly vulnerable to heat under relatively mild conditions. Malignant hyperthermia susceptibility (MHS), predisposed by mutations in the skeletal muscle calcium release channel (RYR1), is one of the most severe heat-related illnesses. The MHS-associated heat susceptibilities predominantly affect children and metabolically active young adults, often leading to life-threatening hypermetabolic responses to heat. However, the mechanisms underlying this enhanced susceptibility to heat, especially among vulnerable populations, remain to be elucidated. Brown adipose tissue is a specialized thermogenic organ that has an established physiological role in maintaining body temperature in infants and regulating energy balance through adulthood. In contrast, the pathophysiological role of brown fat thermogenesis in hypermetabolic conditions has not been explored. Here we show that brown adipose tissue thermogenesis as a potent regulator of hypermetabolic response to heat in the preclinical mouse model with an MHS-associated Ryr1Y524S (Y524S) mutation. Specifically, physiological and pharmacological stimulation of brown fat exacerbates heat sensitivity. Conversely, physiological inactivation, genetic ablation, and pharmacological inhibition of brown fat ameliorate the severity of heat response in Y524S mice. Further, we demonstrate that the heat-sensitive Y524S mutation in the RYR1 channel increases muscle calcium cycling and energy demand at rest, activates the energy-sensing AMP kinase (AMPK) and glycolysis in muscle, leading to a marked increase in circulating lactate. Muscle-derived lactate mediates the crosstalk between muscle and fat and increases brown adipogenesis in preadipocytes systemically, which increases the capacity of brown fat for adaptive thermogenesis via the mitochondrial uncoupling protein (UCP1), primarily upon chronic exposure to cold. We conclude that brown adipose tissue thermogenesis exacerbates the heat-sensitivity as a crucial component of the feed-forward cycle of heat-induced hypermetabolic response associated with MHS. While brown adipose tissue is crucial for maintaining core body temperature and energy balance, brown fat adaptive thermogenesis can be detrimental to the hypermetabolic response to heat. This study demystified the variability of enhanced susceptibility to heat in mice and uncovered why children and metabolically active individuals with MHS are more susceptible to the life-threatening responses to heat. We suggest simple lifestyle interventions by maintaining in constant thermoneutral conditions could minimize the risk of severe heat response and can be potentially life-saving for MHS patients.
Wang, Hui J, "The Molecular Mechanisms and Clinical Implications of Skeletal Muscle Calcium Release Channel Mediated Systemic Thermoregulation Associated with Malignant Hyperthermia" (2020). Texas Medical Center Dissertations (via ProQuest). AAI28151836.