UNDERSTANDING MUSCLE

Mechanisms of contraction

Contraction is the essential function of skeletal striated muscles, which are responsible for the movements of the skeleton. These movements are essential to the interaction of the body with its environment and are controlled by the somatic nervous system.

Cellular and molecular mechanisms of contraction

Contraction of skeletal striated muscle depends on the prior excitation of muscle fibres by motor neurons. This excitation ultimately leads to the thin and thick filaments sliding against one another. The events that take place between excitation and contraction are known as excitation-contraction coupling.

Generation of the muscle fibre action potential

The muscle fibre action potential that gives rise to contraction is generated at the motor endplate through nerve stimulation. When an action potential reaches the axon terminal, the nerve membrane depolarises. This depolarisation opens voltage-gated calcium channels (that is, channels sensitive to the difference in potential between the plasma membrane of the motor neuron and the synaptic space).

The flow of calcium into the axon terminal triggers the fusion of acetylcholine vesicles with the membrane, which releases this neurotransmitter into the synaptic cleft.

Acetylcholine diffuses across the cleft and binds to specific receptors located in the postsynaptic membrane. These receptors are receptor channels. The binding of two acetylcholine molecules to the receptor therefore changes its conformation, which opens the channel. An influx of sodium ions into the muscle fibre depolarises the membrane, producing what is known as the endplate potential.

When this potential reaches a threshold value, it opens voltage-gated sodium channels in the sarcoplasm, thereby generating an action potential. This action potential propagates along the surface of the muscle fibre in both directions towards the ends of the fibre, as the neuromuscular junction is located at the centre of the muscle fibre.

Excitation-contraction coupling

Excitation-contraction coupling is only possible because of the excitability of the muscle plasma membrane. The sarcoplasm is able to generate and propagate action potentials through mechanisms similar to those observed in neurons. In the skeletal striated muscle fibre, the action potential lasts 1 to 2 ms. It ends well before the mechanical signs of contraction appear, and the mechanical activity that follows can last 100 ms or more.
Excitation-contraction coupling takes place at the triad. It requires the involvement of several proteins: calsequestrin, calcium channels, ryanodine and the dihydropyridine receptor. The action potential initiated at the motor endplate travels step by step through the opening of voltage-gated sodium channels, distributing the depolarisation to the transverse tubules (T-tubules), which depolarise in turn and trigger the release of calcium ions from the sarcoplasmic reticulum into the cytosol of the muscle fibre.

This release of calcium ions takes place through the involvement of two types of calcium channel:

i/ the dihydropyridine receptor, located in the membrane of the T-tubule, is a voltage-gated calcium channel;
ii/ the ryanodine receptor, located in the membrane of the sarcoplasmic reticulum, is a calcium ion release channel.

Dihydropyridine and ryanodine are associated with their respective receptors. Some of the calcium ion release channels are directly associated with the voltage-gated calcium channels. Those calcium ion release channels that are not associated with voltage-gated channels are opened by the influx of calcium into the cytosol. Their opening is stimulated at low intracytosolic calcium ion concentrations (below 0.1 mM) and inhibited at higher concentrations (0.5 mM).
The flow of calcium from the sarcoplasmic reticulum into the cytosol therefore follows two pathways.

  • The first pathway involves a change in the conformation of the voltage-gated channel during depolarisation. This allows the voltage-gated calcium channel to open. This physical change is transduced to the calcium ion release channel.
  • The second pathway involves the opening, by the calcium ions themselves, of the calcium ion release channels that are not associated with dihydropyridine receptors.

Once the action potential has passed, the voltage-gated channels close again and the calcium is recycled, returning to the sarcoplasmic reticulum through the calcium ATPase pumps located in the membrane of the sarcoplasmic reticulum.

Molecular mechanisms of contraction

The molecular mechanisms of contraction in the strict sense begin as soon as calcium is released into the cytosol.

Within the myofibrils, the available calcium ions bind to troponin C. This binding shifts the troponin-tropomyosin complex from its position on the actin filament.

This movement thereby exposes binding sites for the myosin heads. Note that at rest, in the absence of ATP, the myosin heads are attached to the actin filament and form a cross-bridge, which gives the muscle its rigidity.

Once the myosin binding sites on the actin filaments are exposed, each myosin head binds to a molecule of ATP. This binding causes the myosin heads to detach from the actin filament.

Then, during the ATP hydrolysis phase, the myosin heads pivot and bind to actin at the binding sites. The release of the inorganic phosphate (Pi) produced by ATP hydrolysis causes a change in the conformation of the myosin heads.

The movement produced by this change in conformation displaces the actin filament, resulting in a shortening of the sarcomere.

The subsequent release of ADP allows the cross-bridge between actin and myosin to re-form.

This cycle repeats several times (9 to 12 times) for as long as calcium remains bound to troponin.

Meanwhile, the calcium ATPase pumps recycle calcium from the cytosol back into the sarcoplasmic reticulum by hydrolysing ATP into ADP + Pi. The fall in calcium ion concentration within the cytosol causes the calcium-troponin C complexes to dissociate.

Tropomyosin returns to its initial position through a change in the conformation of the troponin-tropomyosin complex.

The binding sites on the actin filament are therefore no longer available, which brings about relaxation and a return to the resting state within the myofibril, and the fibre relaxes.

ATP use and synthesis

ATP is required for the muscle fibre to contract and relax, through:

  • the binding of ATP to myosin, which is required for the myosin heads to detach from the actin filament;
  • the hydrolysis of ATP, which provides the energy needed for the movement produced by the “rotation” of the myosin heads;
  • the hydrolysis of ATP at the calcium ATPase pump, which allows relaxation by recycling calcium.

To sustain contractile activity, ATP molecules must be supplied by metabolism as fast as they are broken down by the contractile process. This is achieved through three main metabolic pathways: the alactic anaerobic pathway, the lactic anaerobic pathway and the aerobic pathway.

Synthesis via the alactic anaerobic pathway

ATP can be resynthesised from phosphocreatine (PCr) via the alactic anaerobic pathway, also known as the phosphagen pathway. This synthesis follows the chemical reaction:

ADP + PCr –> ATP + creatine

This synthesis takes place at the start of exercise.

Synthesis via the lactic anaerobic pathway

The second synthesis pathway (lactic anaerobic, or anaerobic glycolysis) involves the breakdown of glycogen (the storage form of glucose) into pyruvic acid. This pathway yields three ATP molecules from one molecule of glycogen. These reactions do not require the presence of oxygen (more precisely, molecular oxygen). They lead to the formation of lactic acid, whose accumulation disrupts contractile processes.

This metabolic pathway is mainly involved at the start of exercise, when the oxygen supply is insufficient, and during intense exercise, when the aerobic pathway no longer provides enough energy.

Synthesis via the aerobic pathway

The aerobic glycolysis pathway and the fatty acid breakdown pathway involve the breakdown of carbohydrate and lipid substrates in the mitochondrion in the presence of oxygen, ranging from the formation of 37 ATP molecules from the breakdown of one molecule of glycogen to the synthesis of 390 ATP from the breakdown of one lipid molecule.