Rhabdomyolysis Pathophysiology
What is Rhabdomyolysis and what are its causes?
Rhabdomyolysis is the destruction of the muscle cell and the release of its contents into the bloodstream [1]. Many of the cases of rhabdomyolysis go undiagnosed because its severity can vary greatly. However, it is estimated that 26,000 cases occur in the U.S. per year [2]. The many causes of rhabdomyolysis (listed below) result from an imbalance in ATP requirement as compared to ATP production. This ultimately leads to destruction of the cell membrane itself, or other chemical and energetic imbalances. Of the causes listed, we will focus on rhabdomyolysis induced by over-exertion.
Causes of Rhabdomyolysis[1]:
-Exertion/Exercise
-Crush injuries
-Car accidents
-Infection
-Drugs
-Toxins
-Endocrine abnormalities
-Other myopathies
-High temperature and high humidity environments
What goes wrong with the muscle cells?
(interference of control system)
The ability to understand how cell pathways and properties lead to rhabdomyolysis is vital for treating this pathophysiology. As explained on the "skeletal muscle physiology" page, the muscle utilizes various energy mechanisms to sustain activity, whether in contraction, extension or during isometric activity [3]. ATP, creatine kinase and the balance of ions all play a role in muscle activity. What happens when your muscle can no longer supply the ATP needed to continue or can no longer utilize creatine kinase for activity and the ionic balance is not maintained? These are the questions we will answer.
If a person over exerts muscles in the body to the point when there is no longer ATP to create energy, the cross bridge cycle shown below in Figure 1 is disrupted. As shown, the cross-bridge cycle requires the hydrolysis of ATP to create ADP and Pi for the ratcheting motion caused between the actin and myosin filaments [1]. Another process that is disrupted is the ion balance. In rhabdomyolysis, the calcium ion concentration outside of the cell is greatly increased. This increased concentration gradient leads to a large influx of calcium into the cell disturbing the cell's ability to maintain ionic equilibrium [4]. The reuptake of calcium by the sarcoplasmic reticulum (SR) is energy dependent on ATP as shown below in Figure 1 [3]. Without ATP and with a large influx, calcium concentration continues to increase in the intracellular space.
Increased calcium influx also greatly affects the mitochondria. As shown in Figure 2, mitochondria have calcium channels. One channel that is affected by the increased cytosolic calcium (Ca2+ cyt) leading to its dysfunction is the sodium calcium exchanger. This leads to a large influx of calcium and activation of proteolytic enzymes that are normally dormant, consequently leading to swelling and eventual lysis of the cell [5]. In this case, calcium activates the proteolytic enzyme Calpains [6]. These proteolytic enzymes begin to degrade the cell membrane, leading to a less viscous, more permeable membrane and increases the diffusive capability of the intracellular contents. Seppet et al. discusses the mitochondrial enzymes, pyruvate dehydrogenase (PDH), isocitrate dehydrogenase, and 2-oxoglutarate dehydrogenase, but does not connect them necessarily with cell death [5]. The typical necrotic cell death is caused by the swelling, membrane degradation and release of the intracellular contents (potassium, phosphate, aldolase, myoglobin, creatine kinase, lactate dehydrogenase, aspartate transferase and urate) into the circulatory system [4].
What is the problem with release of intracellular contents? Don't muscles break down during exercise all the time? Yes, but not to the extent of rhabdomylosis. Of particular interest is myoglobin, an oxygen carrying protein much like hemoglobin, but it contains only one heme group and consequently can only bind one oxygen molecule. It helps the cell store additional oxygen for excessive exercise and aids in oxygen diffusion across the cell [3].
So that is a lot of verbiage about pathways and cells to explain rhabdomyolysis. Check out the flow loop, equation explanation and video below to get a better understanding. Also, click on the "Signs and Symptoms" link to learn what to look for if you think you have rhabdomyolysis. Afterwards, you can try your luck at the rhabdomyolysis quiz!
How does Rhabdomyolysis Effect the Flow Chart Equations?
Step 1: The equilibrium of ATP to ADP and P changes with a lowering of ATP due to its depletion.
Step 2: The permeability P increases and the intracellular calcium concentration (Ci) increases, changing the current (I) due to the large influx of calcium.
Step 3: The thickness of the membrane (δ) decreases, permeability (p) increases and diffusion (D) increases.
Step 4: Since diffusion (D) increases, the time (t) to travel λ distance decreases.
Step 5: The creatine kinase levels (Scr) increase due its release with the intracellular contents.
The FDA shows normal creatine kinase levels in males and females to be 38-174 and 96-140 U/L respectively. During rhabdomyolysis these levels can increase to 500-1500 IU/L.
Also, if more than 100 grams of muscle tissue is broken down, the plasma binding capacity is breached leading to unbound myoglobin in the bloodstream [4].