Skeletal muscle plasticity and thermogenesis: Insights from sea otters

Comment on: Wright T, Davis RW, Pearson HC, Murray M, Sheffield-Moore M. Skeletal muscle thermogenesis enables aquatic life in the smallest marine mammal. Science. 2021;373: 223–225.

Various morphological and metabolic adaptations have equipped mammals to survive diverse habitats including extreme differences in temperature. For homeothermic mammals in cold habitats, insulation is critical to minimize heat loss. However, when insulation is not sufficient, metabolism is increased to generate heat through increased activity, shivering, or other regulated increases in metabolic rate. As a result, there are vast adaptive differences in insulation, temperature tolerance, and metabolic thermogenesis among different mammal species (e.g. tropical vs. polar mammals), and among the same species in different geographic regions (e.g. northern vs. southern populations and low-altitude vs. high-altitude populations). Moreover, metabolic acclimatization is also critical within an individual animal during seasonal, diurnal, and habitat shifts. Thus, an animal’s ability to tolerate varied environmental temperatures can be shaped by both short-term acclimatization and evolutionary adaptation via changes in morphology (e.g. body size and insulation) and metabolism (e.g. upregulated metabolic thermogenesis) [1].

Although morphological differences between species may be relatively obvious and easily quantified, it is more difficult to identify tissue and cellular level adaptations that influence metabolic rate. Aerobic metabolism in mammals is supported by the integration of respiratory and circulatory systems and regulated at the cellular level by numerous interconnected molecular pathways. Given the complexity of integrative metabolism, the expression or function of a single gene is not responsible for setting a predetermined basal metabolic rate in the whole animal or the metabolic capacity in any one tissue [2]. While it may be difficult to identify the primary mechanisms regulating whole-body metabolism in mammals, the Krogh principle teaches us that studying unique animal models can yield novel insights into resolving this physiological “problem.” Studying hypermetabolism in cold-adapted mammals provides a model of adaptive metabolic plasticity to identify tissues with the ability to respond to changing metabolic demand and pinpoint the associated cellular pathways.

Mammalian basal metabolic rate (BMR) is a combined aggregate of tissue-level metabolism. Because assorted body tissues differ in mass and metabolic rate, their individual contributions to BMR and thermogenesis are varied [3]. Skeletal muscle makes up the largest single tissue in most mammals, and although the specific metabolic rate of skeletal muscle (metabolic rate per kg of tissue) is low at rest, it has a high maximal respiratory capacity. This means that skeletal muscle has a large metabolic scope that is not utilized at rest, but has tremendous metabolic and thermogenic potential. The large relative mass also means that even small perturbations in muscle metabolic rate have profound effects on whole-body metabolism and thermogenesis [4].

Although the metabolic rate in resting skeletal muscle is low, it can rapidly increase to support metabolic demand. In skeletal muscle, this increased demand often powers muscle contractions for movement during physical activity, but can also increase for thermogenesis. Increased metabolic heat production can result from shivering (thermogenic muscle contractions that do not support functional movement), or nonshivering thermogenesis. Nonshivering thermogenesis has the advantage of not requiring muscle contraction to increase cellular energy expenditure. Instead, the sequestration of ions in membrane-bound intracellular chambers is made less efficient by “leaky” membranes. This leak requires additional energy expenditure to maintain trans-membrane concentration gradients, and includes proton leak across the inner mitochondrial membrane (where the proton gradient is used to generate ATP) as well as sarcolipin-mediated leak of sequestered calcium from the sarcoplasmic reticulum [4]. Through these mechanisms, skeletal muscle tissue contributes significantly to thermogenesis. Skeletal muscle metabolic capacity must be maintained at a level adequate to support not only thermogenesis, but also peak simultaneous demands for sustained physical activity and cellular maintenance. While increased demand for physical activity (e.g. endurance exercise training) is recognized as the primary work-producing stimulus to upregulate skeletal muscle aerobic capacity, the role of cold exposure is often underappreciated for its ability to stimulate an upregulation of metabolic capacity and thermogenic leak.

Marine mammals are a diverse group. Although not all derived from the same evolutionary lineage, these mammals share common aspects of their life history, having evolved to live and feed in/on the world’s oceans. Because water draws heat away from the body much faster than air, it is particularly challenging for marine mammals to stay warm. To cope with the thermoregulatory challenge of aquatic life, many marine mammals have a thick layer of blubber for insulation and a large, streamlined body that reduces surface area for heat transfer [5].

Sea otters are the smallest of the marine mammals. Lacking the large body mass and thick blubber common to many marine mammals, they instead rely on fur for insulation (Fig. 1). Sea otters have the densest fur of any mammal, however, thermogenic hypermetabolism is still required to maintain a stable core body temperature in the cold water. As a result, sea otters have a resting metabolic rate about 3 times greater than predicted for their size. Although sea otters are established models of thermogenic hypermetabolism, the tissue-level source of this additional metabolism was previously unknown. Given that skeletal muscle is the primary source of adaptive thermogenesis in large mammals [4], we explored sea otter skeletal muscle metabolism using high-resolution respirometry. We discovered that sea otter skeletal muscle has an unusually high capacity for thermogenesis at rest by short-circuiting mitochondrial respiration from ATP production with uncoupled leak metabolism [6]. In addition, we found that neonatal sea otter skeletal muscle respiratory capacity was identical to adults, despite their muscle being physically immature.

Fig 1.

Thermally-challenged sea otters have both metabolic and morphological adaptations for life in cold water. Photo Credit: Heidi Pearson. Image obtained under USFWS Marine Mammal Permit No. MA-043219 to Randall Davis.

The high leak rate and precocious development of sea otter skeletal muscle metabolism indicate that thermogenesis is a determining factor for the development of metabolic capacity in these animals. However, it is not clear if the precocious development and high leak capacity in neonatal skeletal muscle are the result of evolutionary adaptation or either prenatal or rapid postnatal acclimatization to cold stimulus. Notably, toward the end of gestation, pregnant sea otters experience a declining resting metabolic rate and an associated decrease in body temperature [7], and this decreased maternal body temperature could potentially serve as a stimulus for fetal metabolic development. Thus, this curious prenatal metabolic circumstance in late sea otter gestation may represent an early cold stimulus needed to trigger cold acclimation.

Expanding our appreciation of skeletal muscle beyond its basic role of generating movement is critical to understanding how an ecological parameter such as ambient temperature affects animal physiology, metabolism, and physical performance. Our recent work utilizing sea otters as a novel animal model of hypermetabolism emphasizes the critical importance of metabolic plasticity in skeletal muscle to meet the metabolic demands faced by mammals for endothermy and energy balance. This work also illustrates how manipulation of skeletal muscle metabolism (e.g. either up to stimulate weight loss or down to reduce body wasting) offers tremendous potential to improve human health and disease. Seeking a more complete understanding of how mammals use morphological and metabolic adaptations to survive extreme temperatures, the hypermetabolic thermogenesis of sea otters elegantly demonstrates the importance of skeletal muscle metabolic plasticity, and re minds us that physiological ecology can also guide our clinical perspective of human health and disease.