The image for May in our 2018 calendar captures a molecular snapshot of one of our primary groups of organs – the muscular system. Here we discuss the individual molecules responsible for the large motions of these muscles.

The muscular system is the chief workhorse of our body, containing around 700 muscles and making up roughly half of our body weight. Muscle is the only tissue in the body that has the ability to contract, and therefore controls all body movements. The muscular system is also responsible for maintenance of posture and movement of substances inside the body, for instance in pumping blood or moving food through the digestive tract. As a by-product, muscle tissue can also generate heat, particularly useful when you’re cold as shivering is an attempt to generate heat by working the muscles.

How do muscles work?

Muscle is a soft tissue composed of myocyte cells, also known as muscle fibres. Within each myocyte are myofibrils which are composed of two types of proteins filaments; actin, tropomyosin, and troponin make up the thin filaments while myosin forms the thick filaments. These filaments are further arranged into repeating units called sarcomeres, which are the contractile, functional units of the overall muscle.

It is the interaction of myosin with actin filaments that results in muscle contraction. The best proposed model for understanding muscle contraction is the sliding filament model, investigated in these structures from Gurel and Alushin in 2017. In this model, actin and myosin proteins pull themselves past one another within the sarcomere, resulting in a contraction that changes both the length and shape of the cell.

The interaction of myosin and actin is highly regulated by the calcium-binding proteins tropomyosin and troponin. When calcium concentration in the sarcomere is low, troponin locks tropomyosin in a position that blocks the myosin-binding site. This stops actin from moving along the myosin molecules, therefore preventing contraction of the sarcomere. When signals for muscle contraction arrive via nerve impulses, calcium is released from the sarcoplasmic reticulum into the sarcomere. Binding of calcium to troponin causes a conformational change, uncovering the myosin-binding sites on actin. The myosin head then attaches to the actin filament, enabling contraction to proceed by a mechanism referred to as a ‘power stroke.’ This process involves the release and rebinding of actin by myosin molecules as they ‘walk’ along the actin filament. This leads to movement of the thick and thin filaments relative to each other, resulting in a shortening of the sarcomere and muscle contraction.

^{Image showing structure of the complex of actin, myosin and tropomyosin. The electron microscopy map is shown at the bottom left and the fitted structural model at the top right.}

The ‘power stroke’- the movement of myosin along actin filaments is predominantly caused by large conformational changes powered by hydrolysis of ATP. ATP binds to the cross bridges between myosin heads and actin filaments, releasing the interaction between these molecules. The energy from hydrolysis of ATP to ADP then powers the movement of the myosin head to a position further along the actin filament. Release of ADP increases the affinity of myosin to bind actin, resulting in the binding to actin in the new position. Rapid rebinding of ATP leads to myosin dissociation from the actin filament and a new cycle is started. As muscles store very little ATP, yet use a lot, the mitochondria of these cells continuously generate ATP, using the products from the breakdown of sugars as the final step in respiration.

^{Image showing the ATP/ADP binding site in the overall complex (top right) and zoomed in on the binding site (bottom left). The ADP molecule is shown in predominantly red in ball and stick representation and the calcium as a green sphere.}

Structural details and artwork

The structure featured on the calendar for May is inspired by PDB entry 4a7l, a complex of actin, tropomyosin and myosin resolved by cryo-electron microscopy to 8A resolution.

The artist Ryan Hutchinson from Impington Village College beautifully shows the actin filaments using Batik technique on silk fabric.