Research Blog

Accelerating Skeletal Muscle Injury Regeneration

Man holds a leg in a cast

Muscle injuries are common in athletics, but there are steps to take to enhance recovery. Rest, ice, compression and elevation followed by specific muscle regeneration training have been shown to aid in muscle injury recovery. In addition, a study highlighting a novel biochemical means of speeding regeneration.

Muscle damage injuries are prevalent in athletes and, after strains, are the second leading cause of sports-related injuries (Muscle contusion injuries: current treatment options, 2001.  Beiner JM, Jokl P). A significant blow to muscle tissue can damage the muscle. Football players, by the nature of their sport, suffer a high frequency of muscle injuries. However, muscle damage is not limited to athletes because a severe impact will injure the muscle whether in the midst of competition or not. Nonetheless, a speedy regeneration of muscle tissue is likely of most consequence to the elite athlete.

Muscle injury symptoms include loss of muscle resistance and swelling at the injury site. It is important to understand how a muscle regenerates following injury. The diagram below illustrates the process of muscle healing. At day 2 following muscle injury macrophages remove broken muscle fibers while fibroblasts begin generation of connective scar tissue.  At day 3 satellite cells start regeneration of muscle tissue (a process that naturally occurs with muscle building as mentioned in a previous post on Exercise Medicine). By day 5 myoblasts have joined into tubes that will become active muscle fibers. On day 7 the myofibers begin protruding through the scar tissue formed by the fibroblasts. By day 14 the scar tissue is further reduced by regenerating myofibers. At day 21 days post-injury the connective scar tissue is nearly diminished by the fused muscle fibers.

muscle injury and regeneration

Although short-term treatment options for muscle injuries are well described in scientific literature, the sports medicine community has not agreed on a "one-size-fits-all" approach to long-term treatment (Muscle injuries: optimizing recovery, 2007. Tero Jarvinen, et al.). Although doctors used to prescribe muscle immobilization for muscle injuries, this is not common practice anymore due to the deleterious effects of continuous disuse. Instead, immobilization is recommended for the first 5 to 7 days following the injury.  Immobilization is succeeded by controlled use. Immediately following muscle injury, the protocol recommended is referred to as RICE: rest, ice, compression and elevation. Icing of the damaged area reduces inflammation. Elevation means keeping the damaged muscle above the heart to reduce blood pooling. The goal with all four treatments is to reduce the developing gap between damaged muscle tissue. This is accomplished by reducing interstitial fluid and bleeding at the internal injury site.

Three different muscle strengthening programs are recommended following initial recovery for controlled use of the muscle. The first training technique is isometric training and is to be commenced 3-7 days following muscle injury.  Isometric training is when tension increases but the muscle length remains constant. There is no joint movement. The load can be increased with muscle recovery. Once isometric training can be performed, pain-free isotonic training can be initiated. Isotonic training means the muscle length changes but the resistance on the muscle remains constant. The third training to be performed is isokinetic training, whereby the speed of the joint is constant. This is accomplished with special machines that vary resistance with the task.

An interesting study published last summer found that increased VEGF in the injured skeletal muscle of white rabbits improved muscle recovery (VEGF Improves Skeletal Muscle Regeneration After Acute Trauma and Reconstruction of the Limb in a Rabbit Model, 2012. Frey SP, et al.). VEGF, Vascular Endothelial Growth Factor, induces the proliferation of blood vessels or angiogenesis. The researchers treated rabbit limbs to ischemia (reduction of blood flow was accomplished with a tourniquet). Two interesting results came out of this study.  First, it was found that VEGF treatment accelerated the return of muscle force.  Second, VEGF treatment decreased resulting connecting tissue 40 days post-muscle damage. Recall that the connective tissue in this case is a form of scar tissue that is lost with muscle regeneration. The figure below shows the increase in muscle force in VEGF treated rabbits (top line) and rabbits not treated with VEGF (bottom line).

Muscles regenerate faster when treated with VEGF

However, as the authors note VEGF is expensive and human application cannot necessarily be extrapolated from rabbit models. In the meantime, if you are injured or treating someone injured the best bet is to follow the RICE plan followed by controlled strength training.

Why You Lose Fitness Slower Than You Think

A muscle fiber.

Muscle fiber increase in myonuclei during training is not lost during succeeding detraining and may explain the quick increase in muscle mass during retraining, termed "muscle memory".

Detraining is the phase that occurs after one stops training. Of course, when you stop working out for an extended period of time you lose fitness. However, you may be surprised at how quickly you regain that lost fitness when you resume working out months, or even years, later.  Studies have shown this phenomenon is not just in your head, it actually exists.  In fact, one study found that elderly participants in a two year resistance training program retained significant fitness after three years of detraining (Two years of resistance training in older men and women: the effects of three years of detraining on the retention of dynamic strength, 2003. Smith, et al.).  In addition, studies have found that you regain fitness faster during a retraining regimen following a detraining phase than the initial training regimen. One study showed that women who trained for twenty weeks regained muscle mass faster following 32 weeks of detraining (about 7.5 months)  than women who did not participate in the initial twenty week training program (Strength and skeletal muscle adaptations in heavy-resistance-trained women after detraining and retraining, 1991.  Staron, et al.)

The ability to quickly regain muscle mass lost during detraining is termed "muscle memory." (This term is not to be confused with muscle memory in regards to performing a specific task such as swinging a baseball bat or typing, which stems from development in the motor cortex region of the brain.) According to research published several years ago, this muscle memory may stem from increased muscle fiber (myocyte) nuclei (Myonuclei acquired by overload exercise precede hypertrophy and are not lost on detraining, 2010.  Bruusgaard, et al.).

Muscle cells are one of the few multi-nucleated cells in the mammalian body. In response to training, the muscle fiber increases in size. This increase in size is matched by an increase in myonuclei. Each new nucleus in the myocyte is incorporated from the fusion of a neighboring satellite cell. The figure below shows data from the Bruusgaard experiment demonstrating an increase in myonuclei following muscle overload. 

Number of nuclei per IIb fiber from the EDL in normal (Con.) and overloaded (Overl.) muscle. ***Statistical significance (P < 0.0001).

The researchers tagged the new nuclei produced in the muscle overload. Surprisingly, these new nuclei did not die during muscle denervation (disconnection of muscle from nerve, rendering the muscle useless) following the overload. During retraining the muscle fiber increases in size; however, new nuclei are not necessary for the increase in muscle fiber volume. This suggests that muscle nuclei may serve as the mechanism of muscle memory. During retraining the nuclei are already present so hypertrophy (an increase in muscle mass) occurs quickly. The proposed "muscle memory" mechanism is shown in the figure below.

A model for the connection between muscle size and number of myonuclei. In this model, myonuclei are permanent. Previously untrained muscles acquire newly formed nuclei by fusion of satellite cells preceding the hypertrophy. Subsequent detraining leads to atrophy but no loss of myonuclei. The elevated number of nuclei in muscle fibers that had experienced a hypertrophic episode would provide a mechanism for muscle memory, explaining the long-lasting effects of training and the ease with which previously trained individuals are more easily retrained.

This is a novel explanation to why we can regain muscle so quickly. Muscle fiber nuclei produced in training are not lost during extended periods of rest allowing the individual to quickly regain lost muscle mass during retraining. This must provide comfort to athletes forced to miss extended periods of training due to injury.

The Role of Exercise on Insulin Sensitivity


The physiology behind exercise's role in controlling diabetes: burns fat, increases insulin-independent glucose uptake and increases capillary proliferation.

Type II diabetes occurs when the body fails to regulate its body's glucose levels.  The failure can occur at many points in the body. The pancreas may fail to produce sufficient insulin, the liver may fail to release glucose into the blood, endothelial tissue lining the capillaries may fail to take glucose out of the blood or the cells themselves may fail to take up glucose. It is important to get glucose to the skeletal muscle because the body stores nearly 80% of its glucose as muscle glycogen. Insulin and its antagonist glucagon control blood glucose levels by stimulating the liver to take-up or release glucose or by triggering peripheral cells to take glucose out of the blood. If insulin fails to do its job, either because it is not produced or because peripheral cells lose their insulin sensitivity, the body's cells will not take up glucose even with high blood sugar levels. This is why diabetes is described as "starvation in the midst of plenty." The cells are starving for energy even as blood glucose levels rise.  When glucose is too high in the plasma the kidneys filter it out with the urine because the kidneys cannot maintain such a high glucose osmolarity gradient.  Exercise controls type II diabetes through several mechanisms: it decreases fat stores, increases insulin-independent glucose uptake in the muscle and increases the amount of capillary surface area for glucose uptake in skeletal muscle.

Excess fat tissue has long been known to decrease insulin sensitivity.  This is why obesity increases the risk of diabetes. Exercise obviously burns off fat and thus can reduce diabetes risk this way.

In the 1980's it was reported that exercise increased muscle glucose uptake independent of insulin (Increased Muscle Glucose Uptake After Exercise: No Need for Insulin During Exercise, 1985.  Richter EA, et al.) Researchers discovered that the exercise-induced increased insulin-independent glucose uptake remained after the exercise bout was complete. The figure below demonstrates how muscle glucose uptake increases with increasing exercise intensity and duration.

cycling increases glucose uptake

Leg glucose uptake at rest and during cycle ergometer leg exercise at different power outputs Skeletal muscle glucose uptake increases substantially during dynamic exercise. The increase is dependent mainly on exercise intensity but also on exercise duration.    

The mechanism by which exercise increases glucose uptake independent of insulin has been worked out in the last decade (Skeletal Muscle Glucose Uptake During Exercise: How is it Regulated? 2005. Rose AJ and Richter EA). It is now known that the primary glucose transporter responsible for the increased glucose uptake in skeletal muscle fibers is GLUT4. Researchers believe the mechanism may be that the calcium influxes in the muscle that primarily stimulate muscle contraction also trigger GLUT4 to the cellular membrane to increase uptake of glucose. The figure below shows the pathway glucose takes from the blood stream to muscle fiber. Glucose diffuses out of the capillary and into the interstitial fluid. The rate limiting step is glucose uptake via GLUT4.  Once inside the cell, glucose is phosphorylated for glycogenesis (synthesis of glycogen, the myocyte's primary means of storing glucose) or glycolysis (catabolic process that generates ATP to be used immediately for energy).

Glucose transport from the capillary to the myocyte involves diffusion across the capillary wall and facilitated transport with GLUT (glucose transporter enzyme).

Glucose transport from the capillary to the myocyte involves diffusion across the capillary wall and facilitated transport with GLUT (glucose transporter enzyme).

A study that was released late last year found that exercise increases insulin sensitivity through capillary proliferation in the muscle (Muscle-Specific VEGF Deletion Induces Muscle Capillary Rarefaction Creating Muscle Insulin Resistance, 2012. Bonner JS, et al.). In this study the scientists used mice with VEGF expression knocked out in cardiac and skeletal muscle at day sixteen of development. VEGF, or Vascular Endothelial Growth Factor, produces angiogenesis (capillary proliferation) in the skeletal muscle and is released in response to aerobic exercise. The researchers found that when insulin levels were controlled in these knockout mice they had a harder time regulating their blood plasma glucose levels. The researchers concluded that VEGF increases insulin sensitivity and glucose uptake in skeletal muscle. The authors suggest that increased muscle blood volume and capillary surface area for the delivery of insulin and glucose to skeletal muscle fibers may help regulate hyperinsulinemia.

While it is obvious that exercise controls diabetes, it is interesting to know how exercise accomplishes this. It is likely that there are many other mechanisms not mentioned here because the medical community or this author is not aware of them yet. If you have more ideas, share a comment!

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