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Characteristics and consequences of mitochondrial dysfunction fatigue in skeletal muscle

Those who have mitochondrial dysfunction of the skeletal muscle can experience two main types of fatigue. One is the result of increased acidosis inside the muscle cells and has as a marker increased lactate in the blood. This is a result of muscle cells trying to create ATP when there is insufficient oxygen. Endurance athletes (such as marathoners) can experience this type of fatigue. They refer to it as “hitting the wall." 8, 9 It is also referred to as “metabolic fatigue.” 46

The second type of fatigue is the result of a large build-up of Reactive Oxygen Species (ROS) and depletion of ATP in the muscle cells. As far as we can determine from a careful search of the medical literature, this second type of fatigue is unique to patients with known inherited genetic mitochondrial diseases of skeletal muscle, AIDS patients undergoing treatment with antiretroviral drugs (who have severe mitochondrial dysfunction), 47 and ME/CFS patients experiencing post-exertional “malaise.” It is this second type of fatigue that has the most permanent serious consequences for patients.

The first type of fatigue, metabolic fatigue, feels like a burning, dull aching weariness in muscles. The affected muscles feel stiff and affected limbs feel heavier and heavier, as the ability of the muscles to contract declines. 49 The increased acidity in the muscle cell lowers the sensitivity of the contractile apparatus to calcium Ca2+. It is unclear what exact role lactic acid has in this process, but increased lactate in the blood is a marker for this type of fatigue. 46

As mentioned in the preceding section, a subgroup of ME/CFS patients have an abnormal rise in lactate with minor exercise and a very slow recovery from this condition. 30, 32, 35, 38, 48 It is not unusual for these patients to require 24-48 hours or more of bed rest to fully recover. Even in healthy people, delayed onset muscle soreness (DOMS) occurs with severe muscle tenderness as well as loss of strength and range of motion, usually reaching a peak 24 to 72 hours after the “extreme” exercise event that caused the excessive lactate in the blood. 49 (Healthy people don’t have to retire to bed to recover, however.)  Exercise physiologists still do not understand why DOMS occurs, but most research points to actual muscle cell damage and an elevated release of various metabolites into the tissue surrounding the muscle cells. 49 These lead to an inflammatory repair response that lasts a couple of days in healthy people. 49 How long it lasts in ME/CFS patients who have excessive lactate after very little exercise is unknown. For some ME/CFS patients, just standing up for 10 minutes is enough to create this problem. It should be noted that excess lactic acid is now known to be neurotoxic, so continual problems with this could lead to the death or damage of motor neurons in skeletal muscle. 50

The more serious type of fatigue is the one resulting from excessive build-up of ROS in the muscle and depletion of ATP. This type of “fatigue” is extreme prostration that occurs 8 or more hours after exercise (or what passes for “exercise” in ME/CFS patients and would be considered normal activity by healthy people.) Patients feel a deep, whole-body weariness and feel the necessity to lie still and not move due to extreme fatigue. Trying to even turn over in bed requires a great deal of painful effort of will. In addition, patients feel very sore all over their bodies. ME/CFS patients often describe this as feeling being beaten up and run over by a Mack truck or bus. The term post-exertional “malaise” seems pathetically inadequate as a descriptor of this feeling.

Mitochondrial specialist Dr. Donald Johns 51 has warned that when a patient feels this way, it is very important to listen to his/her body. The extreme fatigue feeling is from depletion of ATP and the beaten-up/run-over feeling is from excessive ROS that not only did permanent damage to muscle cells, but also is still doing damage. Thus, it is essential to stay in bed and move as little as possible until the condition improves—even if that takes days. The best thing to do is for the patient to try to avoid getting into this condition in the first place by pacing and staying inside his/her “energy envelope.” This is not so easy to do at times, however.

ROS produced in the mitochondria damage mitochondrial DNA, for instance. 3 This leads to alterations to the polypeptides encoded by the DNA. A decrease in electron transfer then ensues, but electron transfer is needed for generation of ATP. Thus, more ROS are produced in a vicious circle of oxidative distress and energetic decline. 52 Mitochondrial DNA damage also results in daughter cells that are mutated and in cellular apoptosis. 4, 5,  6, 7,  28

Muscle inflammation and oxidative stress are now known to play an important role in muscle atrophy. 53 In addition, many ME/CFS patients have a low-grade fever, which means they have high levels of interleukin-1 (IL-1). 54, 55 IL-1 is known to cause muscle catabolism (muscle destruction). 54, 55 So ME/CFS patients with high levels of ROS and low-grade fevers can expect noticeable destruction of skeletal muscle with difficulty in replacing it.

ROS generated from mitochondria also damages proteins and lipid in membrane components for mitochondria membranes and cellular membranes. This results in more mitochondrial dysfunction and cellular apoptosis. 4, 5, 6, 7, 28

All in all, ME/CFS patients need to try to avoid post-exertional malaise as much as possible in order to avoid permanent damage and permanent adverse changes to skeletal muscle.