The role of skeletal‐muscle‐based thermogenic mechanisms in vertebrate endothermy

Abstract

Thermogenesis is one of the most important homeostatic mechanisms that evolved during vertebrate evolution. Despite its importance for the survival of the organism, the mechanistic details behind various thermogenic processes remain incompletely understood. Although heat production from muscle has long been recognized as a thermogenic mechanism, whether muscle can produce heat independently of contraction remains controversial. Studies in birds and mammals suggest that skeletal muscle can be an important site of non-shivering thermogenesis (NST) and can be recruited during cold adaptation, although unequivocal evidence is lacking. Much research on thermogenesis during the last two decades has been focused on brown adipose tissue (BAT). These studies clearly implicate BAT as an important site of NST in mammals, in particular in newborns and rodents. However, BAT is either absent, as in birds and pigs, or is only a minor component, as in adult large mammals including humans, bringing into question the BAT-centric view of thermogenesis. This review focuses on the evolution and emergence of various thermogenic mechanisms in vertebrates from fish to man. A careful analysis of the existing data reveals that muscle was the earliest facultative thermogenic organ to emerge in vertebrates, long before the appearance of BAT in eutherian mammals. Additionally, these studies suggest that muscle-based thermogenesis is the dominant mechanism of heat production in many species including birds, marsupials, and certain mammals where BAT-mediated thermogenesis is absent or limited. We discuss the relevance of our recent findings showing that uncoupling of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) by sarcolipin (SLN), resulting in futile cycling and increased heat production, could be the basis for NST in skeletal muscle. The overall goal of this review is to highlight the role of skeletal muscle as a thermogenic organ and provide a balanced view of thermogenesis in vertebrates.

Increased Reliance on Muscle-based Thermogenesis upon Acute Minimization of Brown Adipose Tissue Function

“…We propose that SLNmediated uncoupling of SERCA leads to an increase in cytosolic Ca 2ϩ and activation of CaMKII by phosphorylation at Thr 286 . Phosphorylation of RyR1 increases Ca 2ϩ leaking from the SR, increasing SERCA activity, setting up a leak reuptake cycle analogous to the functioning of the heater organ in endothermic fishes (21). Based on our data and results published previously, it seems possible that activation of CaMKII is a coldinduced, Ca 2ϩ -sensitive molecular response conserved in diverse life forms (40).…”

“…[13][14][15][16][17][18][19] and reviewed in Ref. 20,21). Recently, we reported that modulation of SER Ca 2ϩ cycling by sarcolipin (SLN) in skeletal muscle plays an important role in NST (13,14,(22)(23)(24).…”

Cold adaptation overrides developmental regulation of sarcolipin expression in mice skeletal muscle: SOS for muscle-based thermogenesis?

“…Collectively, these findings along with our data suggest that SLN is an important marker of muscle-based thermogenesis. Interestingly, SLN is expressed abundantly in adult skeletal muscles of large mammals including dog, rabbit and pig, which contain only negligible amounts of or non-functional BAT (Rowland et al, 2014), indicating that muscle-based NST may play a greater role in such animals. Therefore, determining the physiological relevance of high levels of SLN in these species will be instrumental in better understanding muscle-based NST.…”

Uncoupling Protein 1 and Sarcolipin Are Required to Maintain Optimal Thermogenesis, and Loss of Both Systems Compromises Survival of Mice under Cold Stress

“…Further, with muscle being dispersed throughout the body, it can provide heat locally, rather than needing to be circulated by the blood from a localized BAT. Hence, during the evolution of endothermy in individual species, a combination of BAT and muscle-based thermogenesis has been selected that provides the best survival outcome (13).…”