An Overlooked Form of Non‐Shivering Thermogenesis in Skeletal Muscle

Abstract

The taxonomic class of mammals is characterized by its ability to produce milk, but several other features distinguish mammals from their reptile ancestors. A debated hallmark that has attracted much attention, shared with birds, is endothermic homeothermy—the capacity to maintain a high and stable body temperature independent of environmental heat sources—which reptiles generally cannot do. Endothermy is an expensive undertaking that requires the ability to increase and control the rate of metabolic heat generation [1]. To retain the metabolic heat, mammals also evolved external insulation, notably in the form of fur, and did so before they evolved the ability to give birth to live young, as evidenced by the endothermic monotreme mammals having fur but being egg layers. Reproduction might have been a factor in the evolution of endothermy because some python species [2] and the tegu [3] have some capacity for endothermy, but only in their reproductive phases. In unstressed inactive mammals most metabolic heat is the waste heat generated by cellular biochemical processes, the energetics of which is measured as the basal metabolic rate (BMR). BMR of mammals generally is about 10 times that of reptiles. No specific organ or tissue is responsible for that “constitutive” heat production. Ion pumps are ubiquitous and intrinsically inefficient, and their activity releases waste heat in all cells. Leakier membranes in mammalian than in reptile cells, leading to a requirement for elevated activity of ion pumps, can explain much of the elevated BMR of mammals over reptiles [4]. When a mammal is exposed to cold, the rate that heat is lost from the body to the environment can be alleviated by peripheral vasoconstriction. Many reptiles also seem to adjust their rate of environmental heat gain/loss by adjusting peripheral perfusion [1]. If vasoconstriction fails to arrest the fall in body temperature, mammals increase metabolic heat production to match the rate of heat loss [5, 6]. The “extra” thermogenesis adds to the cost of living, but presumably those costs are outweighed by the advantages of defending the high and stable body temperature. Whether endothermic homeothermy evolved via a selection pressure for the advantages of high and stable body temperature, or a selection pressure that favored some other facet of biology that ended up being correlated to a high body temperature, such as aerobic capacity [1], is still debated. More is known about the mechanisms of thermogenesis, in the form of shivering and non-shivering thermogenesis. Shivering thermogenesis does not occur in reptiles but is well characterized in humans and other mammals. Shivering involves rhythmic, involuntary, uncoordinated contraction of skeletal muscle fascicles that are made up of individual muscle cells (myocytes) [7]. The first type of non-shivering thermogenesis (NST) to be discovered involves the activation of brown adipose tissue (BAT). Normally, mitochondria use a proton gradient generated across the inner mitochondrial membrane by proteins of the electron transport chain (ETC) to phosphorylate ADP to ATP. That terminal phosphate bond in ATP is the energy currency of cells and provides the power for all cellular activities. BAT cells express a unique protein, uncoupling-protein-1 (UCP1), in mitochondria. When UCP1 is activated, the proton gradient is dissipated, and the energy that is generated by the ETC and stored in the proton gradient no longer is captured in ATP but appears as heat. That heat can obviate the need for shivering, especially in neonatal mammals [8]. In the past, UCP1 was considered essential for NST. But over the years, other heat generating processes have been discovered that do not involve contraction of skeletal muscle or activation of UCP1. Aside from its role in shivering thermogenesis, skeletal muscle can contribute significantly to NST via a futile cycle that consumes energy but produces no nett work or synthesis of any product. When an action potential sweeps across the membrane of a myocyte, a change in the conformation of the dihydropyridine voltage sensor that is connected to the ryanodine receptor on the sarcoplasmic/endoplasmic reticulum triggers the release of Ca2+ ions into the cytosol. In the cytosol, those ions bind to troponin and trigger cross-bridge cycling in the myocyte via the interaction of actin with myosin. If sufficient myocytes are activated in synchrony, the muscle will develop tension and then shorten. Relaxation of the muscle occurs when the sarco/endoplasmic reticulum calcium ATPase (SERCA) pumps the Ca2+ from the cytosol back into the sarcoplasmic reticulum. In some conditions, Ca2+ can leak from the sarcoplasmic/endoplasmic reticulum in quantities that are not high enough to trigger cross-bridge cycling but are sufficient to trigger the activity of SERCA. So Ca2+ is pumped back into the reticulum without there ever having been a change in the mechanical state of the muscle, but the cycle generates heat in the inefficient process of ion pumping [9]. BAT cells share a common embryological origin with myocytes and also contain SERCA. SERCA activation generates heat in them too, and the process is independent of UCP1 [10]. While shivering involves whole muscles, only individual fascicles are asynchronously activated and contract; the muscle itself does not shorten and performs no external work. The activation of a fascicle removes slack, but not over the entire muscle. All energy derived from the hydrolysis of ATP by myosin ATPase, which fuels tension development and shortening in normal muscle function, appears as heat. A general increase in electrical tone of the muscle as well as the depolarizations that lead to the uncoordinated contractions are usually included in “shivering”, but according to Njå and Lømo [11] in this issue of Acta Physiologica, they derive from different processes in skeletal muscle. They recorded electrical activity from skeletal muscles in the core and periphery of rats placed into an elevated, sprung tray with force transducers at each corner. The transducers detected all movement of the rats and could be used to identify periods when there was no overt physical activity, including shivering or breathing. Ambient temperature was then decreased from 32°C to 2°C. In the absence of any movement, the tonic electrical activity in external muscles depended strictly on ambient temperature, rising and falling with ambient temperature. In contrast, the tonic electrical activity in the internal muscles (iliacus and psoas) did not vary with ambient temperature but increased when the rats were recovering from the hypothermia caused by general anesthesia. How much heat the myocyte activity generated, without those muscles doing any external work, remains to be established. We probably should not be surprised that redundant mechanisms have evolved for a process as important as thermoregulation in endotherms, as they have for the control of appetite [12]. Redundancy provides a significant evolutionary advantage for survival but does make the complex of processes difficult to decipher. Studies like that by Njå and Lømo will help us to understand, eventually, the complex of processes that evolved when selection for a high and stable body temperature occurred. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.