Mechanistic insights on muscle fatigue in ageing adults

Ageing is associated with a reduction in self-sufficient mobility and general physical capabilities. It is assumed that reduced physical abilities in ageing adults are the result of a loss of muscle mass and a reduced ability to produce mechanical power. Fatigability, comprising an acute reduction in muscle power output, is a critical factor involved in the age-associated decline in physical abilities. Loss of muscle mass and fatigability create an additive problem to the functional abilities of an ageing adult when performing moderate- to high-velocity exercise. Such age-associated changes pose a significant problem for older adults, interfering with and limiting their performance of daily activities, as well as increasing their risk of injury and further physical impairments. Although changes to physical abilities and muscle function in ageing adults are well-known, the mechanisms responsible for muscle fatigability are not as well understood and remain to be clarified. As reported in The Journal of Physiology, Sundberg et al. (2019) have investigated two hypotheses exploring potential mechanisms responsible for age-related muscle fatigue. First, their study explored whether a loss in mechanical power during fatiguing exercise experienced by older adults is the result of lower muscle oxidative capacity compared to younger adults. Second, dynamic fatiguing knee extension exercises were used to examine whether loss of mechanical power in ageing adults is associated with the accumulation of metabolites [i.e. hydrogen (H+), inorganic phosphate (Pi) and diprotonated phosphate (H2PO4−)] in an active muscle. These metabolites have been shown to reduce force production and it is considered that they inhibit cross-bridge functioning of the sarcomere and excitation-contraction coupling. To test these hypotheses, seven young adults (six females and one male) and eight older adults (seven females and one male) were studied between the ages of 20–23 and 68–87 years, respectively. Participants underwent various knee extension exercise protocols performed with their dominant legs to measure mechanical performance and fatigability. Phosphorus nuclear magnetic resonance spectrometry was used to measure muscle oxidative capacity and metabolite accumulation in the muscle during exercise performance. During the dynamic fatiguing exercise, participants were instructed to kick every 2 s for 4 min with maximal effort against a 20% maximal voluntary isometric contraction load. The older adults had 47% less mechanical power at the start of this exercise compared to the younger participants. Furthermore, muscle fatigability during this protocol was ∼1.8-fold greater in the older adults compared to the younger adults. These results were important because they demonstrated that older adults not only have less mechanical power, but also, during exercise, muscle power declines at a greater rate compared to younger adults. With contraction, ATP concentration is conserved through buffering by phosphocreatine (PCr), via the creatine kinase reaction. Resynthesis of PCr is dependent on the production of ATP via oxidative phosphorylation. Accoridingly, PCr recovery kinetics were measured following 24 s of maximal voluntary isometric contractions to estimate the muscle oxidative capacity of the participants. No differences in muscle oxidative capacity measurements were observed, indicating that there were no differences in the ability of the participants' muscles to utilize oxygen and produce ATP, despite significant differences in old compared to young adults. Concentrations of Pi, H+, and H2PO4− in the active muscle were all significantly greater in the final 64 s of the dynamic fatiguing exercise in the older compared to younger adults. Importantly, the accumulation of all of these metabolites at the end of the exercise protocol was strongly associated with fatigability and a decreased pH of the surrounding tissues. These results expand on previous work conducted by Sundberg et al. (2018a) in which the effects of increased metabolite levels were examined on single muscle fibres isolated from muscle biopsies of both young and older adults. Further strengthening the argument of the current study, it was found that elevated metabolite levels resulted in decrements in single fibre contractile function. Moreover, the results showed that muscle fibres from both the young and older adults equally experienced decrements in contractile function in the presence of elevated metabolite levels. According to the results of the current study, although there are no differences in muscle oxidative capacity of the knee extensors between younger and older adults, there is a significant age-associated increase in accumulated metabolic by-products that correlates with the reduced mechanical power experienced by older adults. This suggests that the higher levels of accumulated metabolites that are known to induce functional impairments at the sarcomere are probably responsible for the greater muscle fatigability observed in older adults. Although this is indeed an important finding, why specifically older adults had a greater metabolite accumulation in their active muscle still remains unclear. A possible mechanism that may be responsible for these differences comprises changes in the functioning of the skeletal muscle membrane transport systems, such as the Na+/H+ exchanger, which work to restore and maintain pH levels. Impairments to such systems limit the ability of muscles to reduce intracellular H+ concentrations after exercise-induced increases, allowing for sustained acidic environments. A second possible mechanism is that the muscles of older adults may simply require more ATP to achieve the same work output as younger muscles, which would result in a greater Pi accumulation. Future studies could attempt to address these questions by testing the functioning of transport systems in skeletal muscle, as well as how much ATP is utilized during muscle contraction in both younger and older adults. Noteworthy is that mainly female participants were used in the current study as a result of strength-related measurement difficulties. Specifically, the scanner used to perform the tests was not able to withstand the muscular strength that was associated with the males’ performances. Interestingly, previous analyses have demonstrated sex differences in muscle fatigue during the performance of (i) slow- but not high-velocity contractions of the elbow flexor muscles and (ii) isometric fatiguing muscle contractions of the knee extensor muscles, such that women generally experience less fatigability than men (Hunter, 2016). It is hypothesized that such sex differences are mainly a result of differences in contractile mechanisms between men and women (Hunter, 2016). Thus, the previous literature suggests that sex differences exist in relation to muscle fatigability, although this is dependent upon the specific task being performed (i.e. specific to the velocity of the contraction or which muscle is being used to perform a certain task). In support of this theory, another recent study that examined the fatigability of the knee extensor muscles in young, old and very old men and women performing high-velocity concentric contractions found no sex differences in muscle fatigability within the different age groups (Sundberg et al. 2018b). Further studies are warranted to clarify and confirm any possible differences in muscle fatigability between males and females, as well as how ageing may impact these differences. Overall, the results reported by Sundberg et al. (2019) indicate that older adults experience both reduced mechanical power and increased muscle fatigability during fatiguing exercises relative to younger adults. Furthermore, these differences in older adults are suggested not to be a result of differences in muscle oxidative capacity. Instead, a greater accumulation of metabolic products in the working muscle is considered to be linked to impaired physiological activity of muscle fibres (i.e. impaired sarcomere activity and excitation–contraction coupling) and thus skeletal muscle function. These are novel results that help to further clarify the mechanisms responsible for the decreases in muscle functioning with age. It is important to understand the mechanisms via which muscle ageing and fatigability occur so that preventative and possible treatment options can be explored. Furthermore, these results will guide future research aiming to more deeply investigate precisely why metabolite accumulation in the working muscle is increased in older adults and, overall, how these differences are related to muscle fatigability and impaired function. No competing interests declared. RF and CR were responsible for the conception or design of the work. RF and CR were responsible for the acquisition or analysis or interpretation of the data. RF and CR were responsible for frafting the work or revising it critically for important intellectual content. Both authors agree to be accountable for all aspects of the work and approved the final version submitted for publication. RF is currently funded by an NSERC graduate student award. The lab is also currently funded by NSERC through RF and CR's supervisor, Dr. Rebecca MacPherson.

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