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Exertional Rhabdomyolsis: When Too Much Exercise Becomes Dangerous
Mike Deyhle & Len Kravitz, Ph.D.

Rhabdomyolysis (RM) literally means the breakdown of striated muscle (Landau et al., 2012). While this definition is a broad one, RM is more commonly used to describe a syndrome characterized by muscle protein and sarcolemma (muscle cell membrane) breakdown and spillage of muscle-specific contents into the circulatory system. Reports of RM date back thousands of years (Vanholder et al., 2000). More recently, cases of RM were documented after the Sicilian earthquake in 1908 and in the German military literature after the First World War (Giannoglou et al., 2007). British physicians Eric Bywaters and Desmond Beall reported cases of RM in bombing victims in 1940.

RM resulting in elevated levels of muscle proteins in the blood (notably myoglobin) can lead to potentially life-threatening complications including acute renal failure, blood clotting, and hyperkalemia (an elevation of potassium in the blood that may lead to an abnormal heart rhythm). While causes of RM are myriad, exercise induced or exertional RM (ERM) has been shown to be the most frequent cause of RM-related hospitalization (Alpers and Jones 2010). Given the seriousness of this syndrome and the fact that exercise is a potential trigger, ERM should be on the minds of fitness professionals when working with any client. This review will provide the personal trainer with the pathophysiological (functional changes that accompany a particular syndrome) knowledge of ERM, how to recognize ERM, and give known situations when risk of ERM is increased.

Pathophysiology of ERM: Too Much Cellular Ca2+ Becomes a Problem in Muscle
The causes of ERM are many. Intense exercise, a crushing injury, blood restriction to tissues, and some drugs may all lead to ERM. Despite the wide range of causes, loss of intracellular ionized calcium (Ca2+) homeostasis (internal equilibrium) seems to be a common event with all causes (See Figure 1). Ca2+ is housed in a special reservoir of tissue in muscle, known as the sarcoplasmic reticulum. It serves as a trigger for muscle contraction. Increases in sarcoplasmic calcium concentrations following intense muscle contraction initiates a cascade of events that result in muscle cell damage and the spilling of some proteins into the blood. The abnormally high Ca2+ concentrations activate the release of protein degrading enzymes (calpains) and sarcolemma degrading enzymes (phospolypase A2) (Allen et al. 2005). These enzymes weaken the sarcolemma which increases it's permeability (Allen et al. 2005). This increased sarcolemma permeability may then lead to the leakage of potentially harmful proteins into the blood.

Exertional Exercise and Rhabdomyolysis
The increase in sarcoplasmic Ca2+ release following exertional exercise appears to be (at least in part) due to stretch activated ion channels (SACs) (Allen et al., 2005). As their name implies, SACs, which are located on the sarcoplasmic reticulum, become activated by mechanical stretch with load (such as with repetitive bouts of eccentric exercise, intense exercise or high-repetition exercise). Activated SACs allow the flow of several cations (positively charged minerals) including Ca2+ into the cell fluid (sarcoplasm) (Allen et al., 2005). Landau et al. (2012) report that consistent exercise risk factors for developing ERM appear to be low baseline fitness levels and early introduction of highly repetitive exercises (e.g. squats, push-ups, sit-ups). The authors continue that a common factor in ERM seems to be exertion beyond the point when fatigue would compel an individual to naturally stop. Landau and colleagues (2012) report examples of extreme exercise leading to ERM where persons were exposed to doing100's of push-ups in an afternoon or “squat jump syndrome”, where the exercises were told to squat as low as possible and then jump as explosively as possible repeatedly until exhaustion. The authors observe that although extreme exercise loading is most associated with ERM, it can occur from seemingly 'safe' exercise too, because some people are just more physiologically vulnerable. Importantly to personal trainers, exercising in hot environments predisposes exercisers to ERM, so always monitor clients carefully during workouts in heat conditions.

Eccentric Exercise and Rhabdomyolysis
The SACs are particularly prone to activation by eccentric contraction. During eccentric contractions a muscle is being stretched when it is trying to contract. SACs activated by eccentric contractions that leads to a dramatic increase in sarcoplasmic Ca2+ may explain why exercise induced muscle damage is most associated with eccentric exercise (Landau et al., 2012).

Uniquely, skeletal muscle is exceedingly responsive to demands imposed upon it. The impressive plasticity of skeletal muscle is exemplified in the phenomenon known as the repeated bout effect (RBE). As explained in a previous IDEA Fitness Journal Article (Bubbico, A. & Kravitz, L. (2010). Eccentric exercise. IDEA Fitness Journal, 7(9), 50-59) the RBE is the observation that skeletal muscle rapidly adapts to this eccentric exercise stress when the eccentric exercise is introduced at much LIGHTER intensities up to a week before completing higher intensity eccentric training. The targeted muscles prepare protective mechanisms that reduce cellular Ca2+ spillage and degrading protein leakage. Thus less chance for ERM to present.

Signs and Symptoms: Introducing the ERM Triad
Only a doctor can diagnose an individual with RM. However, early detection is important. This is why fitness professionals should be alert to early signs of the syndrome so that he/she may refer the client to a medical professional for prompt diagnosis.

A typical triad of symptoms includes reddish brown (cola colored) urine, muscular pain, and weakness. Reddish brown urine may indicate myoglobinuria (the presence of myoglobin in the urine) and can be a powerful diagnostic tool of RM (Giannoglou et al., 2007). Reddish brown urine, however, is only present in about half of RM cases. Therefore, its absence does not rule out the possibility of RM (Giannoglou et al., 2007). Unfortunately, muscular pain and weakness is non-specific, subjective and is commonly experienced following intense and/or unaccustomed exercise without adverse events. Additionally, symptoms of muscle stiffness and swelling may occur with RM (Giannoglou et al, 2007).

Taken together, the fitness professional should suspect the possibility of ERM if clients report ongoing muscle soreness and weakness following exercise. If the client reports reddish brown urine the fitness professional should immediately refer the client to a medical professional.

Fitness Level and Too Much Unaccustomed Exercise Make A Difference with ERM
The fitness level of the client is particularly important to consider when designing a workout or program (Landau et al, 2012). In other words, what type, how long and how much (if any) exercise training has the client done in the past to prepare him/her for the ensuring workout? ERM may occur when the individual is unaccustomed and unprepared for the mode or intensity of the exercise. So, the combination of an entry level client attempting to do an extreme conditioning program could easily be the precise precursor for ERM.

Practical Application: Avoiding ERM
Fitness professionals understand the importance and effectiveness of high intensity training. However, it is important for the exercise professional to carefully utilize the principles of initial fitness level and progressive overload when designing an exercise program so that the exercise stress is at the appropriate challenging for the client. This will be particularly imperative when the client is new to exercise, returning to exercise after a hiatus, or when embarking upon a new training phase or novel training stimulus. Extra care should be taken when the exercise is performed in hot environments, introducing eccentric exercise and when a client has any genetic factors described in Side Bar 1.

Intense repetitive exercise or eccentric training may overstretch the sarcoplasmic reticulum
Leads to
Increase in Calcium ion leakage into muscle cell
Leads to
Activation of sarcolemma (cell membrane) degrading enzymes
Leads to
Increase in sarcolemma permeability
Leads to
Release of harmful proteins in blood that may cause renal failure, blood clotting, heart arrhythmias
Figure 1. Pathophysiology of Rhabdomyolysis
Adapted from Landau et al., 2012

Side Bar 1: Genetic Factors Rhabdomyolysis
Some genetic differences may predispose individuals to experience RM. Many of these genetic differences result in the deficiency of enzymes important in ATP production or calcium handling. According to Landau et al. (2012), the most common inherited genetic alterations that are known to increase risk of RM are the following:
1) McArdle disease: McArdle patients may have an increased risk of developing RM because of reduced ability to utilize glycogen to make ATP.

2) Carnitine polmitoyl transferase II (CPT2) deficiency: CPT2 is and enzyme required for long chain fatty acids to enter the mitochondria (ATP synthesis factory) where they may be broken down for energy. Individuals with genetic deficiencies in CPT2 appear to have an increased risk of RM because of reduced ability to produced ATP from fat.
3) Myoadenylate deaminase (AMPD) deficiency: AMPD is an enzyme that is important for reformation of ATP. Individuals with a genetic deficiency in AMPD may have an increased risk of RM because of reduced ability to reform ATP during intense exercise.

Mike Deyhle, B.S, CSCS, is an Exercise Science masters student at the University of New Mexico, Albuquerque. His research interests include exercise induced muscle damage and signal transduction in exercise physiology. Mike is a former gymnast who enjoys rock climbing, cycling and playing classical guitar.

Len Kravitz, PhD, is the program coordinator of exercise science and a researcher at the University of New Mexico, where he won the Outstanding Teacher of the Year award. He has received the prestigious Can-Fit-Pro Lifetime Achievement Award and was chosen as the American Council on Exercise 2006 Fitness Educator of the Year.

Allen, D.G, Whitehead, N.P, and Yeung, E.W. (2005). Mechanisms of stretch-induced muscle damage in normal and dystrophic muscle: role of ionic changes. Journal of Physiology, 567.3, 723-735.
Alpers, J.A., and Jones, L.K. (2010). Natural history of exertional rhabdomyolysis, a population-based analysis. Muscle & Nerve, 42, 487-491.
Giannoglou, D.G., Yiannis, S.C, and Misirli, G. (2007). The syndrome of rhabdomyolysis: Pathophysiology and diagnosis. European Journal of Internal Medicine, 18, 90-100.
Landau, M.E, Kenney, K., Deuster, P., and Campbell, W. (2012). Exertional rhabdomyolysis: A clinical review with a focus on genetic influences. Journal of Clinical Neuromuscular Disease, 13(3), 122-136.
Vanholder, R., Sever, M.S, Erek, E., and Lameire, N. (2000) Rhabdomyolysis. Journal American Society of Nephrology, 11: 1553-1561.