Professor Roger Cooke’s vision for skeletal muscle’s super relaxed state: a conceptual paradigm shift for naturally managing metabolic diseases including obesity

Professor Roger Cooke is remembered for his extensive work on the structure–function relationships of motor proteins, including his landmark discovery of the super relaxed state (SRX). The SRX burns calories an order of magnitude slower than the (regular) relaxed state (RX). In skeletal muscle, this dramatically lowers resting metabolic rate, enabling animals to survive food scarcity, torpor, and hibernation. In humans, the ability of resting muscle to switch between the RX and SRX creates a dynamic metabolic range of ~ 1000 kilocalories (kcal) per day. In natural living systems, myosin in the SRX is mainly ordered within a structure called the interactive heads motif (IHM), whereas myosin in the RX is more disordered, referred to as the disordered relaxed state (DRX). An increased DRX persists after generating force, which is likely the main reason for the profound benefits of regular movement throughout the day. In humans, this includes normalizing blood sugar in type-2 diabetics and eliminating weight gain while overfeeding by 1000 kcal per day. The discovery of the SRX, therefore, creates a paradigm shift in our view of skeletal muscle, bridging the gap between how muscle generates metabolic control and force production. Here, I will describe the key ideas Roger shared with me during our research conversations in the last few years of his life, including thoughts on SRX function (particularly as it relates to the IHM, with insights from recent findings), its regulation (directly by ligands and indirectly by hormones), and its tremendous potential to improve human metabolic health.