Potential cellular and energetic mechanisms for age‐related differences in skeletal muscle fatigue

Skeletal muscle fatigue is defined as the contraction‐induced decline in maximal force‐ or power‐generating capacity and can be caused by failure at any site along the pathway of force production. Several studies have observed greater skeletal muscle fatigue in older compared with young adults during high‐velocity contractions, but the cause of this difference remains unclear. Because activities of daily living, such as climbing stairs or walking, require repeated dynamic contractions, the ability to resist muscle fatigue may be important for maintaining physical function into old age.

Recently, Sundberg et al. (2018b) examined age‐related differences in voluntary activation and contractile properties before and after a fatigue protocol consisting of 80 maximal velocity contractions at 20% maximal isometric force. The authors reported no age‐ or sex‐related differences in voluntary activation before or immediately following the fatigue protocol. However, the age‐related difference in muscle fatigue was strongly associated with the contraction‐induced change in involuntary twitch amplitude (r = 0.75, P < 0.001), suggesting that the age‐related differences in muscle fatigue are determined by mechanisms affecting excitation–contraction coupling or myosin–actin cross‐bridge function.

In a second article, in a recent issue of The Journal of Physiology, Sundberg et al. (2018a) demonstrated greater muscle fatigue in older compared with young men (reduction in power output of 32 ± 12 vs. 12 ± 13%, respectively) in response to 4 min of maximal velocity contractions at 20% maximal isometric force, reinforcing their previous finding that older adults fatigue more than young following high‐velocity dynamic contractions. To identify potential mechanisms for greater muscle fatigue in older compared with young adults, the authors examined the effects of fatiguing conditions on skeletal muscle function at the cellular level using single muscle fibres from the vastus lateralis of young and older men. This study by Sundberg et al. is novel as it is the first to examine skeletal muscle fatigue in human single muscle fibres since all cellular and molecular studies of skeletal muscle fatigue to date have been performed in animal tissue. The present study confirmed previous findings in animal studies by showing that simulating fatigue in vitro (pH 6.2; 30 mm P_i) altered single fibre contractile activity at the cellular level and myosin–actin mechanics at the molecular level. Measures of single muscle fibre function (i.e. specific force production and maximal unloaded shortening velocity) and cross‐bridge function (i.e. myosin low to high force transition) declined similarly in response to muscle fatigue simulated by elevating proton [H⁺] and inorganic phosphate [P_i], two metabolites known to accumulate with fatigue and inhibit contractile function at the molecular level (Debold et al. 2012). They also showed that the contraction‐induced decline in whole muscle power with age was partially attributed to loss of myosin heavy chain (MHC) II muscle. However, despite greater whole muscle fatigue in older vs. young men, single fibre and cross‐bridge function decreased similarly in both age groups, suggesting that greater fatigue in older adults may not be explained by altered single fibre function.

Because this study could not conclude whether the age‐related increase in whole‐muscle fatigue is explained by changes in single fibre or cross‐bridge function, further research is required to better understand the effects of ageing on skeletal muscle fatigue. Sundberg et al. studied only men, and ageing has been shown to affect single fibre and myosin–actin function differently in men and women (Miller et al. 2013). Moreover, some, but not all, research suggests that fatigue‐induced declines in whole muscle power production may be sex dependent, even in young adults (LaBarbera et al. 2013). Therefore, additional work is necessary to examine the effect of sex on age‐related differences in skeletal muscle function and fatigue at the whole muscle, cellular and molecular levels. There are also other aspects of myosin–actin interactions that may help elucidate a molecular basis for the age‐related differences in skeletal muscle fatigue observed in the present study. For example, sinusoidal analysis of single muscle fibres can be used to infer myofilament properties (i.e. myofilament lattice stiffness) and cross‐bridge kinetics (i.e. myosin attachment time and rate of myosin force production), which play a fundamental role in skeletal muscle contraction and are related to single fibre function and whole muscle power (Miller et al. 2013). Using sinusoidal analysis may reveal whether fatiguing conditions affect myofilament lattice stiffness as well as myosin attachment time and rate of force production differently with age, potentially providing molecular mechanisms for age‐related differences in fatigue at the whole muscle level. Lastly, Sundberg et al. simulated fatigue in vitro by lowering pH and elevating [P_i], which are thought to be the primary contributors to fatigue (Debold et al. 2012), although a reduction in calcium (Ca²⁺) release and an accumulation of adenosine diphosphate (ADP) and reactive oxygen and nitrogen species also occurs with fatigue. Therefore, a comprehensive approach that examines the effect of pH and [P_i], as well as other molecules that accumulate (e.g. ADP, reactive oxygen and nitrogen species) or decrease (e.g. Ca²⁺) during fatigue in vivo on single fibre function in young and older adults might help reveal contraction‐related causes of age‐related differences in muscle fatigue at the cellular and molecular levels. Sundberg et al. acknowledged that free myoplasmic Ca²⁺ likely decreases during high‐intensity contractions, indicating that their study cannot eliminate the possibility that greater fatigue in older adults is due to contraction‐induced decrements in single fibre function.

Sundberg et al. postulated that age‐related differences in skeletal muscle fatigue during high‐velocity contractions may be a consequence of an increased accumulation of [H⁺] or [P_i] in older compared with young muscle. Lanza et al. (2005) previously reported a greater relative reliance on oxidative phosphorylation with age during a 60 s maximal voluntary isometric contraction of the dorsiflexor muscles, which resulted in a significantly higher pH and lower [P_i] in older compared with young muscle. However, unlike the dorsiflexor muscles, oxidative capacity of the knee extensors is significantly lower in older compared with young adults (Fitzgerald et al. 2016). The ATP cost of contraction is also higher during dynamic compared with isometric contractions. Thus, the greater ATP cost of dynamic contractions, coupled with a lower knee extensor oxidative capacity, may stimulate a greater recruitment of glycolysis in the knee extensors of older compared with younger adults, leading to a greater [H⁺] and [P_i] and therefore greater muscle fatigue during high‐velocity contractions. To the best of our knowledge, this hypothesis has not been directly tested.

In conclusion, the study by Sundberg et al. (2018a) in The Journal of Physiology offers unique insight into the mechanisms of age‐related differences in skeletal muscle fatigue in humans. To the best of our knowledge, Sundberg et al. have published the first paper examining the potential cellular and molecular mechanisms of fatigue in human single fibres. Their work provides evidence that the contraction‐induced decline in whole muscle power with age is at least partially due to loss of MHC II muscle. Similar to animal studies, [H⁺] and [P_i] slow the transition of the myosin head from the low to high force state in the cross‐bridge cycle and depress fibre power, indicating the importance of these metabolites for fibre function. The authors also found that greater fatigue in older vs. young adults in response to dynamic contractions of the whole muscle could not be attributed to altered contractile function of single fibres with age in response to elevated [H⁺] and [P_i] since contractile function of both age groups was depressed similarly with fatigue. However, further studies are needed to determine whether age‐related differences in the accumulation of [H⁺] and [P_i] exist, or the relative reliance on a given bioenergetic pathway during high‐velocity dynamic contractions. Additionally, Sundberg et al. only included young and older men in their study, and previous research has demonstrated sex differences with age in cross‐bridge function and with fatigue in whole muscle function, indicating a need for studies examining potential age‐ and sex‐related differences in single fibre contractile function during fatigue. Further, a thorough examination of other aspects of myosin–actin cross‐bridge function may help elucidate molecular mechanisms for the age‐related differences in muscle fatigue at the whole muscle level. Overall, this study by Sundberg et al. advances our knowledge about potential mechanisms for age‐related differences in skeletal muscle fatigue in humans and provides a basis for future mechanistic research on fatigue.

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