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The American Geriatrics Society, with support from the National Institute on Aging and the John A. Hartford Foundation, held its fifth Bedside-to-Bench research conference, “Idiopathic Fatigue and Aging,” to provide participants with opportunities to learn about cutting-edge research developments, draft recommendations for future research, and network with colleagues and leaders in the field. Fatigue is a symptom that older persons, especially by those with chronic diseases, frequently experience. Definitions and prevalence of fatigue may vary across studies, across diseases, and even between investigators and patients. The focus of this review is on physical fatigue, recognizing that there are other related domains of fatigue (such as cognitive fatigue). Many definitions of fatigue involve a sensation of “low” energy, suggesting that fatigue could be a disorder of energy balance. Poor energy utilization efficiency has not been considered in previous studies but is likely to be one of the most important determinants of fatigue in older individuals. Relationships between activity level, capacity for activity, a tolerable rate of activity, and a tolerable fatigue threshold or ceiling underlie a notion of fatiguability. Mechanisms probably contributing to fatigue in older adults include decline in mitochondrial function, alterations in brain neurotransmitters, oxidative stress, and inflammation. The relationships between muscle function and fatigue are complex. A number of diseases (such as cancer) are known to cause fatigue and may serve as models for how underlying impaired physiological processes contribute to fatigue, particularly those in which energy utilization may be an important factor. A further understanding of fatigue will require two key strategies: to develop and refine fatigue definitions and measurement tools and to explore underlying mechanisms using animal and human models.

1. To investigate the effect of the female reproductive hormones on muscle function, patients undergoing in vitro fertilization were tested during two phases of treatment. The first was following the downregulation of pituitary gonadotrophin releasing hormone (GnRH) receptors and the second after 9 days of gonadotrophin injections. 2. Maximal strength and fatiguability of the first dorsal interosseus muscle were assessed when oestrogen and progesterone were low, and less than 2 weeks later when oestrogen production reached supraphysiological levels. 3. There were no significant changes in either strength or fatigue resistance during acute, massive fluctuations in oestrogen. These results occurred at a time when progesterone levels remained relatively low. 4. Contrary to previous work, the present results suggest that oestrogen does not affect muscle strength.

Effects of intermittent one leg isometric fatigue on maximal isometric force, force production, relaxation and blood lactate were studied using 29 male students as subjects. The relative changes of variables during fatigue and recovery were intercorrelated together with muscle structure variables, which were determined using needle biopsy technique. Maximal force decreased, force production and relaxation became slower and muscle lactate increased during fatigue. Change of maximal force, force production and lactate during fatigue as well as recovery of maximal force and lactate after fatigue were correlated significantly to muscle fiber distribution. Fatiguability of the force-time characteristics was therefore influenced by the differences in the metabolic profiles of the individual muscle fibers. However, ability to relax the muscle quickly was not observed to be dependent on muscle structure. This suggest that different fatigue mechanisms might be present in relaxation than in force production.

The fatiguability of the quadriceps muscle was investigated in 10 male subjects (25-40 yrs), with inter-individual differences in fibre composition of their vastus lateralis muscles (range 25-65% fast twitch, FT, muscle fibres). Fatiguability was assessed as the decline in maximal force (in % of initial values) with 50 repeated isokinetic knee-extensions at fast angular velocity (3.14 rad/s). Each contraction lasted 0.5 s and the rest periods were about 0.7 s. Every subject was tested on two occasions and the standard deviation for a single determination of fatiguability was 1.4%. The decline in force after 50 contractions was on the average about 45%. The individual values varied, however, and a linear correlation was present between fatiguability and % FT fibres (r = 0.86, p less than 0.01). It was concluded that development of fatigue in human skeletal muscle performing repeated fast dynamic contractions with maximal effort was most marked in muscles with a high proportion FT fibres. This finding was in conformity with earlier results from animal skeletal muscle preparations.

Relaxation rate (RR), half contraction time to tetanus (CTT1/2) and force-frequency curves were investigated in 77 children, aged 9-15 years, using supramaximal stimulation of the ulnar nerve and recording from the adductor pollicis muscle. No sex differences were found in these variables. The RR was independent of age and similar to that in adults. The CTT1/2 was least at the age of 15. The only age-dependent parameter in the force-frequency curves was the relative force developed at a stimulus frequency of 10 Hz, which increased with increasing age. A fatiguability test was performed in 25 children. Reference values for the different parameters are given.

A 6-year-old boy was examined with the dual purpose of establishing whether he had malignant hyperthermia (MH) and to investigate his complaint of excessive muscle fatiguability. In the course of such investigations, McArdle's disease was diagnosed, and the patient was also identified as an MH-positive reactor.

A patient with recurrent attacks of exertional rhabdomyolysis and easy fatiguability was treated with dantrolene sodium. She experienced a complete prevention of myoglobinuric attacks and gained a better exercise tolerance. Biochemical findings in this patient suggest a loosely coupled oxidative phosphorylation in mitochondria. The question is raised as to whether dantrolene sodium exerts an effect on the mitochondrial calcium uptake and influences the state of coupling of the mitochondria.