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Why There’s No Gain Without Pain

Credit: alphaspirit/Adobe

Credit: alphaspirit/Adobe

By Bradley Launikonis

Most people know all too well the feeling of muscle soreness after unaccustomed exercise, but now the cell physiology of the recovery process has been explained.

Our muscles are highly specialised organs that occupy a significant volume of our body mass. They are responsible for our ability to move, to maintain posture, and they allow us to manipulate our environment.

We use our muscles to perform brief, powerful, heavy-lifting tasks, or endurance tasks like long-distance running. These strenuous activities have potentially damaging consequences. Muscles can, for instance, be impaired for extended periods, if not permanently, especially if a heavy load of exercise is unaccustomed to the individual at the time.

In an evolutionary sense, any properties of the skeletal muscle that restricted the ability of our ancestors to escape danger, take opportunities to feed or reproduce must have experienced negative selective pressure. This constant selective pressure to optimise the function of skeletal muscle has caused it to become a highly specialised and versatile organ. For example, our muscles have the ability to fully recover from heavy loads of unaccustomed exercise without a complete loss of the function during the most stressed time when the muscle is vulnerable in the few days following the exercise. This sore and vulnerable period for the muscle is typically known as delayed onset muscle soreness (DOMS).

DOMS is common to most people in the 2–3 days following unaccustomed exercise. In this period of time the muscle is vulnerable to damage because of changes that occur inside the muscle fibres.

However, muscle fibres obtained from runners after a marathon show only minor levels of damage that doesn’t correlate with the soreness experienced by the runners. This suggests that protective mechanisms are most likely at play inside the fibres. Such mechanisms would have to act across the days in which the muscle is sore in order to maintain the viability of as many fibres as possible so the muscle could return to its normal functional capacity quickly. Perhaps in terms of athletic training these days, the maintenance of viable fibres through DOMS should set a new, improved level of strength or performance that is typically expected through consistent training.

What Underlies the Potential Damage Inside Muscle Fibres after Heavy Bouts of Exercise?

Researchers in Denmark have demonstrated that long-distance runners accumulate calcium inside their muscles in a fashion that correlates with the distance covered by the runner. Their work suggested that calcium enters the muscle during muscle activity from the surrounding body fluids, where the level of calcium in solution is relatively high. This is significant because any net change in cellular calcium content will influence many processes in the cell.

In muscle fibres, the major role for calcium is to regulate the generation of force and the relaxation of the muscle. This process is initiated by electrical signals received from neural inputs to the muscle. Excitation of muscle causes a brief rise in calcium as it’s released from an internal membrane-bound store into the bulk area of the muscle fibre. The rise of the calcium transient causes the contraction. The recovery of calcium back into the internal calcium store lowers the bulk calcium levels in the muscle, and this causes the muscle to relax.

However, under conditions where there is a sustained rise in muscle calcium levels, enzymes known as calpains are activated by the high levels of calcium. Calpain activation can initiate remodelling of the fine structures and essential protein–protein interactions that support the conversion of electrical signals in the muscle to contraction. Excessive calpain activation will stop the ability of the muscle to produce force, or could lead to larger-scale damage that may compromise the viability of the fibre.

Who Could This Help?

How the muscle avoids significant and longer-term damage following unaccustomed exercise is of major interest. Understanding what the threshold is for the protective mechanisms to activate during high loads of exercise may help athletes tailor their training regimes so that their peak performance aligns with competition.

From another viewpoint, fundamental understanding of these protective mechanisms may offer the potential for therapy. If it was possible to understand and manipulate protective mechanisms in the muscle, this could be used to help people with muscular dystrophy.

Progressive damage to the muscles is caused by persistently high calcium levels following activity in diseases such as Duchenne muscular dystrophy. The results are a debilitating loss of muscle function.

The key to the protection of healthy muscle following heavy exercise appears to be at the casing of our muscle fibres, the plasma membrane, which is the entry and exit point of calcium to the muscle. The plasma membrane is responsible for maintaining the content and provides a selective boundary and signalling hub that senses the external environment of the cell.

While the majority of the cells in our body are small and round, muscle cells are large and elongated fibres. The reason for the evolution of large and elongated muscle fibres is so that they can be packed with powerful contractile proteins that themselves are highly elongated, specifically for the purpose of generating force. Furthermore, muscle fibres must also extend between connection points with tendons that may be tens of centimetres apart.

The massive size of the muscle fibre causes a problem for the skeletal muscle plasma membrane. It needs to conduct the electrical signal to all parts of the internal environment of the fibre in less than a millisecond to ensure a strong and uniform contraction.

The muscle fibre is built from repeating contractile units known as sarcomeres, each with their own proteins and stores of calcium that need to be stimulated synchronously. The speed with which electrical signals spread around the muscle to induce uniform calcium rise and contraction gives us our ability to move and react.

The T-System

The solution that allowed the plasma membrane to conduct the electrical signal to each sarcomere in the muscle fibres was to send extensions of the plasma membrane into the muscle fibre as tubules that meet the internal calcium store of the fibre in every sarcomere. This creates a unique membrane network known as the t-system. The “transverse tubules” uniformly penetrate from the surface plasma membrane to reach every sarcomere. This makes the t-system a complex and dense membrane network inside the fibre that can maintain the same fluids as the external fluids that surround the muscle and has an interface with virtually all areas inside the fibre.

The t-system is composed of not only transverse tubules but also longitudinal tubules that infrequently connect transverse tubules. The role of transverse tubules in conducting the rapid and uniform contraction of the muscle is clear. However, the role of longitudinal tubules in the muscle appears to be a protective one that is activated in association with DOMS.

In response to unaccustomed exercise causing DOMS, the longitudinal tubules of the t-system swell with water due to osmotic gradients created across the membrane, and become much bigger than their normal size. The new structure created is known as a vacuole.

Many vacuoles form post-exercise, and they take up a significant volume inside the sore muscle. The vacuoles persist for at least 48 hours and disappear within 7 days post-exercise.

The Role of Vacuoles in the Sore Muscle

We have observed calcium movements across the transverse tubular and vacuolar membranes of human muscle fibres obtained from fresh thigh biopsies. Our study, published in Nature Communications (, found that transverse tubules could support the movement of calcium into and out of the fibre in a balanced fashion, but vacuoles only supported the movement of calcium from the bulk area inside the fibre to inside the vacuole. Once calcium was transported from the bulk area of the fibre into the vacuole, it remained there. The vacuoles became calcium sinks, draining the fibre of some calcium. This means that calcium is trapped away from the areas of the muscle where calpains are activated during DOMS.

The greater control of calcium levels inside the bulk area of the muscle fibre prevents excessive activation of calpains in the vulnerable muscle. Calcium remains in the vacuoles until the period of muscle vulnerability has passed after 2–3 days. Vacuoles were also observed to lose their structure to become longitudinal tubules again after the period of DOMS. The normal level of calcium in the muscle fibres is also re-established following the recession of vacuoles.

These latest findings show us that the specialised plasma membrane of skeletal muscle can alter its structure to change the way it handles calcium when the muscle is at its most vulnerable. This prevents the muscle from producing its normally high levels of force, which could cause tension-induced damage, and also prevents the excessive activation of calcium-activated calpains, which would disrupt the mechanisms that allow the conversion of excitation of the muscle to contraction.

The control of calcium levels in the muscle thus preserves the integrity of the majority of its fibres following unaccustomed exercise and DOMS. This explains why recovery is relatively quick when mobility has not been completely compromised after a major load of exercise.

Bradley Launikonis is an Australian Research Council Future Fellow at The University of Queensland’s School of Biomedical Sciences.