Recent Advances in the Understanding of Skeletal Muscle Fatigue

Håkan Westerblad, MD, PhD, David G. Allen, MD, PhD


Curr Opin Rheumatol. 2002;14(6) 

In This Article



Prolonged or repeated contractions of skeletal muscles lead to impaired muscle function, ie, fatigue develops. Fatigue may be caused by factors within the muscle cells (peripheral fatigue) and diminished activation from the central nervous system (central fatigue). The relative importance of peripheral versus central fatigue depends on the type of physical activity. Central fatigue may be more prominent in elderly subjects. Increased concentration of inorganic phosphate seems to be of major importance for acute peripheral fatigue. There is frequently a long-lasting depression of force production after fatiguing muscle activity, especially at low stimulation frequencies. This low-frequency fatigue seems to be due to "structural" changes in proteins involved in intracellular Ca2+ handling. Contractions in which the muscle is stretched (eccentric contractions) cause muscle weakness and damage. The initial defect induced by eccentric contractions is overstretched sarcomeres, but these appear to cause localized membrane tears that subsequently contribute to muscle weakness and damage.


Skeletal muscles are impressive motors that respond rapidly and precisely to commands from the motor nervous system. Skeletal muscle cells can increase their force production up to 40 N/cm2 in less than 100 ms. When unloaded they can shorten at a rate of up to ten muscle lengths/s. However, repeated activation of muscle cells leads to decreased force production and slower contractions, that is, fatigue develops. Fatigue may set in acutely during high-intensity exercise, and it is then mainly caused by factors related to increased energy metabolism. There are also other long-lasting types of fatigue in which metabolic factors appear to be of little importance. Contractions that involve stretch of the muscle also cause muscle weakness and damage, which takes many days to recover from.

Many clinical conditions (eg, heart failure, kidney failure, inflammatory myopathies, chronic arthritis, and aging) are associated with muscle wasting and weakness.[1,2,3] This means that the skeletal muscle cells have to be used closer to their maximum capacity during normal daily physical activities. Thus, while acute muscle fatigue only limits performance during extensive activities (eg, sport activities) in young healthy subjects, it may severely hinder everyday physical activities in people with muscle weakness. For example, walking up stairs may require approximately 30% of the maximal power output of a healthy subject, and some decline in the power output due to fatigue will have little impact. On the other hand, in a patient with muscle wasting and weakness, approximately 90% of the maximal power output may be required, and fatigue will then seriously affect the performance; eg, the patient can no longer reach the top of the stairs.