Neural Mechanisms of Age-Related Loss of Muscle Performance and Physical Function

Abstract

Background: This article discusses the putative neural mechanisms of age-related muscle weakness within the broader context of the development of function-promoting therapies for sarcopenia and age-related mobility limitations. We discuss here the evolving definition of sarcopenia and its primary defining characteristic, weakness.

Methods: This review explores the premise that impairments in the nervous system’s ability to generate maximal force or power contribute to sarcopenia.

Results: Impairments in neural activation are responsible for a substantial amount of age-related weakness. The neurophysiological mechanisms of weakness are multifactorial. The roles of supraspinal descending command mechanisms, spinal motor neuron firing responsivity, and neuromuscular junction transmission failure in sarcopenia are discussed. Research/clinical gaps and recommendations for future work are highlighted.

Conclusion: Further research is needed to map putative neural mechanisms, determine the clinical relevance of age-related changes in neural activation to sarcopenia, and evaluate the effectiveness of various neurotherapeutic approaches to enhancing physical function.

Our population is getting older, and in many regions of the world, more than a quarter of the population is now 65 years or older. Thus, there is a large individual and societal burden linked to age-related disorders. Forty percent of older adults in the United States have physical limitations with daily tasks (1), and preserving physical function drastically reduces healthcare costs and improves the quality of life (2).

The age-related loss of muscle mass, strength, and function, commonly referred to as “sarcopenia,” leads to an increased risk of mobility limitation, falls, loss of independence, disability, metabolic disorders, and mortality (see (3) for further discussion). Most intervention studies to date have focused on various forms of physical exercise and nutritional interventions. However, recent advances in muscle biology have unveiled novel therapeutic targets with several candidate molecules subsequently advancing into human trials. Accordingly, in the spring of 2022, the National Institute on Aging (NIA) organized and hosted a multiday workshop on the “Development of Function Promoting Therapies” that discussed the current landscape of the field, examined biological targets for therapeutic development, and addressed optimal design and expeditious implementation of clinical trials of function-promoting therapies. As part of this workshop, the neural mechanisms of age-related loss of muscle performance and physical function were discussed. In this article, this discussion is summarized within the broader context of the development of function-promoting therapies for sarcopenia and age-related mobility limitations.

Sarcopenia Is Commonly Conceptualized as a Condition of the Muscular System

It is largely assumed that the age-related loss of muscle mass (atrophy) is the predominate cause of the age-related loss of strength, and that mobility limitations manifest when a critical threshold of age-related weakness is reached. Indeed, low grip strength is independently associated with recurrent falls (4) and is a stronger predictor of all-cause and cardiovascular mortality than systolic blood pressure (5). Both low grip and leg extensor strength are associated with mobility impairment (6,7). Muscle weakness is also a biomarker for several negative health outcomes in older adults (8).

However, the physiological mechanisms of age-related weakness are multifactorial, and weakness is only partly due to the loss of muscle mass. For instance, older adults lose leg extensor muscle strength at a two- to fivefold greater rate than they lose quadriceps muscle mass (assessed via computed tomography with intermuscular fat excluded) (9). Substantial strength loss is observed even in older adults who maintain muscle mass over time (9). These findings indicate that the age-related loss of strength is not solely due to muscle atrophy and suggest that neurological and/or nonmuscle mass-related factors are critical in the development of weakness.

The Evolving Definition of Sarcopenia

Muscles are—to a large extent—puppets of the nervous system, which likely explains partially why most of the anabolic therapies investigated to date have not enhanced physical function. Additionally, the Sarcopenia Definitions and Outcomes Consortium, which assembled a large body of data from epidemiologic studies, clinical trials, and special populations, concluded that weakness defined by low grip strength should be included in the definition of sarcopenia as weakness independently predicted falls, self-reported mobility limitation, hip fractures, and mortality in community-dwelling older adults (8). In contrast, lean mass measured by dual-energy x-ray absorptiometry was not associated with incident adverse health-related outcomes in community-dwelling older adults (8). For these reasons, there has been a major shift in recent years in the operational definition of sarcopenia away from low muscle mass to low muscle strength as the key characteristic of sarcopenia (3). There is growing appreciation for the broader neuromuscular mechanisms of muscle force generation and age-related muscle weakness (10).

Do Impairments in the Nervous System’s Ability to Generate Maximal Force or Power Contribute to Sarcopenia?

The deficits in “neural activation” are linked to clinically meaningful weakness for both the hand grip and leg extensor musculature, 2 muscle groups that have strong clinical relevance and robust evidence of weakness mapping to negative health phenotypes in older adults (10,11). Physiological processes involved in voluntary force generation are highly complex. For instance, the nervous system is a cellular network of up to 10 billion neurons and 60 trillion synapses communicating together (12). To execute a purposeful movement, the nervous system must first process sensory information about the body and its surroundings following which the relevant motor centers of the brain and spinal cord generate neural commands (12). The discharge behavior of these neurons, including the motor neurons, represents a complex interplay between the excitatory and inhibitory synaptic inputs they receive and their intrinsic electrical properties (12). Thus, sensory inputs, the descending commands from the supraspinal centers, motor neuronal response in the brain, and the spinal cord are all integrated to enable appropriate body movement (12).

With respect to muscle strength, if the α-motor neurons that excite the extrafusal muscle fibers that are responsible for virtually all the contractile force produced from skeletal muscle are not fully recruited or are not firing at their optimal discharge rates, there will be a “deficit” or an “impairment” in the nervous system’s ability to fully activate a muscle or muscle group (10). The neurophysiological underpinnings of a hand grip task, in particular, are very intricate in that hand grip is a highly evolved task (evolutionary transitions to forceful precision and power “squeeze” gripping occurred ~2–3 million years ago (13)) that involves coordinating 39 different muscles (19 within the hand and 20 in the forearm) synergistically (10). Thus, it is no surprise that a recent genome-wide association study reported that 38% of the 16 loci associated with grip strength were linked to structure and function roles in the central nervous system, peripheral nerves, and/or neuromuscular junction transmission (14). These findings are consistent with other reports indicating that genes known to play a role in neurodevelopmental disorders or brain function, as well as peripheral nerve function, are associated with grip strength (Figure 1) (15). These findings provide evidence for the nervous system being, in part, responsible for age-related declines in muscle strength as well as mobility.

Determining the relative contribution of neural versus muscular mechanisms in age-related weakness is challenging. The most common approach to assaying neural impairments (or deficits) is by comparing maximal voluntary force to maximal electrically stimulated force. The basic premise of these approaches is that volitionally generated force results from a combination of neural and musculotendinous factors, but that during electrically stimulated contractions the brain and certain aspects of the peripheral nervous system are removed from the equation (note that impairments in neuromuscular junction (NMJ) transmission failure would not be detected with these approaches as the series of physiological events involved in NMJ transmission still occur with electrical stimulation).

There are a variety of renditions of these protocols that ultimately give insight into the degree of neural activation. Using a superimposed doublet technique our group has demonstrated that older adults with clinically meaningful leg extensor weakness exhibit notable impairments in neural activation (11). Specifically, we have reported that weak older adults (ie, those whose leg extensor strength to body weight ratio is below a critical threshold shown to be predictive of the future development of severe mobility limitations (7)) have markedly impaired levels of neural activation when compared to older adults who are not weak (Figure 2A) (11). Unfortunately, these protocols cannot be applied to the handgrip due to the large number of innervating peripheral nerves and skeletal muscles involved in the gripping task. As such, partitioning out the relative neural versus muscular contribution to grip strength requires a different approach. The most common approach for the hand grip is to quantify the multi-finger force deficit.

During conventional hand grip strength testing, a dynamometer is held in 1 hand with 4 fingers flexed around a handle. Thus, during a maximal contraction, the peak force recorded is the net force generated by the 4 fingers acting together. What is underrecognized in the sarcopenia field is that the level of neural drive received by the grip force muscles is negatively related to the number of fingers engaged; the maximum force that a given finger can generate decreases in proportion to the number of other fingers that are simultaneously activated. Even in young adults a composite grip strength task (ie, when the 4 fingers are activated together) yields a maximum strength value that is ~30% less than that which can be generated when the fingers are used in isolation (16). This phenomenon, which is well established in the field of motor control, is commonly referred to as the “multi-finger force deficit” and indicates that maximally activating the grip musculature synergistically is a significant challenge to the central nervous system. The multi-finger force deficit is greater in older adults when compared to young adults with deficits of ~50% being reported in independently living, high-functioning older adults (Figure 2B) (16). Notably, females demonstrate very pronounced deficits. For this reason, the multi-finger force deficit is arguably a sensitive index of functional brain integrity (17). It is possible that older adults with sarcopenia or frailty may exhibit even larger deficits in neural activation during grip tasks than healthy older adults. Further, this test is not fully measuring neural deficits in that it does not directly use electrical stimulation to parse out the musculotendinous component per se and relies instead on comparing differences in a composite grip task versus what would be expected based on individual maximal finger contractions when the biomechanical aspects are held constant. It is very likely that this approach underestimates neural deficits. Nonetheless, the fact that high-functioning older adults exhibit such large multi-finger force deficits provides a clear indication of central neural mechanisms heavily influencing hand grip strength values.

The above-mentioned findings suggest that impairments in neural activation are responsible for a substantial amount of age-related weakness. They do not, however, give insight into specific components of the nervous system function that contribute to weakness (eg, central vs peripheral nervous system) nor do they give insight into detailed physiological mechanistic underpinnings. The neural mechanisms underlying weakness are not necessarily synonymous with the neural mechanisms underlying age-related loss of functional mobility. Functional mobility requires an even higher level of skillful and efficient assumption, maintenance, modification, and control of voluntary postures and movement patterns. In fact, we have demonstrated that motor function is considerably more associated with multiple measures of mobility in older adults than both muscle strength and lean mass (18). Additionally, aging appears to affect different muscles in distinctive ways.

The section subsequently describes the effects of aging on (a) cortical/supraspinal descending command, (b) spinal motor neuron firing responsivity, and (c) neuromuscular junction (NMJ) transmission failure.

Supraspinal Descending Command Mechanisms of Sarcopenia

Many aging-related changes are observed in motor cortex morphology, neurochemistry, and excitability. These aging-related changes range from extremely large volumetric reductions in the size of the premotor cortex neuronal cells (19) to reduced white matter mass and the length of myelinated nerve fibers (20). In addition to morphometric changes, neurochemical changes also occur within the basal ganglia, which has been linked to reductions in motor function. For instance, older adults exhibit notable reductions in dopamine receptor densities (~5–10% per decade) (21), which has been linked to reductions in the ability to rapidly generate repetitive muscle contractions (22). We have also reported that dopaminergic genotypes (ie, catechol-O-methyltransferase genotype, which is involved in dopamine degradation), as well as functional connectivity of the medial orbitofrontal corticostriatal network (a dopaminergic influenced network involved in reward processing, motivation, and reward-guided learning) are linked to mobility limitations (23). Additionally, there is prominent age-related degeneration of the corpus callosal fiber bundles connecting nodes of the motor cortical network (10), which has been shown to be related to the degree of physical function responsiveness to a physical activity intervention in community-dwelling older adults who have risk factors for future cognitive impairment (24). Thus, although the findings of this nature have not been causally linked to muscle weakness per se, it seems likely they could affect functional mobility as they likely result in less automaticity of motor tasks and require a greater engagement of attention and cognitive resources.

There is, however, more direct evidence linking reduced cortical excitability to age-related weakness (10). Neural excitability can be defined as the readiness of a nerve cell or circuit to respond to a stimulus. Response is typically in the form of an action potential, which can be measured either individually (single cell) or summed as a compound action potential at the level of a group of neurons or neural circuits. There is strong theoretical support for neural hypoexcitability as a key contributor to weakness. For instance, neurons with low excitability have lower maximal steady-state firing rates (25).

Here, the evidence specific to the intracortical or global corticospinal circuits that were obtained using transcranial magnetic stimulation evoked potentials or through modulation of brain excitability using noninvasive brain stimulation will be briefly discussed. First, older adults demonstrate more than twofold greater level of intracortical inhibition of the wrist flexor primary motor cortex than young adults, and that weaker seniors (lowest tertile of strength) have twofold greater level of intracortical inhibition in comparison to their stronger counterparts (highest tertile; Figure 3A) (26,27). Second, excitatory brain stimulation enhances muscle endurance ~15% of the elbow flexors, with the most robust effects observed in the weakest older adults (28). Excitatory brain stimulation has also been shown to increase hand dexterity in older adults by ~20–25% (29). Older adults with clinically meaningful leg extensor weakness display indices of hypoexcitability when compared to their nonweak counterparts (Figure 3B), and these indices explain approximately one-third of the between-subject variability in muscle strength (which was slightly more than that explained by lean mass) (11). Thus, there is moderately strong evidence to suggest that reductions in motor cortical excitability are linked to age-related weakness.

Spinal Motor Neuron Firing Responsivityand Sarcopenia

The intrinsic motoneuron excitability is reduced in older adults (30). Specifically, Orsatto et al. used the paired motor unit analysis technique to estimate intrinsic motor neuron excitability (30), which is thought to be highly influenced by the persistent inward currents (depolarizing currents generated by voltage-sensitive sodium and calcium channels that increase cell excitability by amplifying and prolonging synaptic input). They observed that older adults exhibited ~35% lower indices of motor neuron excitability in both the soleus muscle group (Figure 3C). Because the persistent inward currents are heavily modulated by the concentration of the monoamines serotonin and noradrenaline, they concluded that their findings are likely explained by either the deterioration of the motoneuron itself and/or the deterioration of the monoaminergic system.

Although this has not been replicated in other muscle groups and it has not been mapped to clinically meaningful weakness, it does, theoretically, seem reasonable as neurons with low excitability have lower firing rates (25). There are several prior studies reporting the motor unit firing rates are slower in older adults than in young adults (see (31) for a systematic review). This prior work, however, has largely stopped short of directly demonstrating that reductions in spinal motor neuron firing rate are linked to age-related weakness per se.

Lastly, selective motor neuron cell death also directly contributes to both muscle weakness as well as muscle atrophy (for recent reviews, see (32,33)). There is significant histological and electrophysiological data indicative of a progressive and irreversible loss of motor units starting slowly at approximately 60 years of age and accelerating with advancing age (32–34). The larger alpha motor neurons are particularly susceptible to cell death (32,33). Muscle fibers regularly undergo cycles of denervation and reinnervation (32,33). Under normal circumstances, the muscle fiber is reinnervated by the original motor axon; however, in instances where the original axon is unable to reinnervate, another motor neuron may compensate and collaterally reinnervate the muscle fiber (32,33). Collateral reinnervation is a compensatory process that mitigates the age-related loss of motor units by preserving muscle fiber innervation; however, not all myofibers are reinnervated and over time both muscle mass and muscle function are negatively affected. Few studies have attempted to parse out the relative contribution of age-related loss of motor units to weakness; however, we have reported that in community-dwelling older adults, the number of estimated functioning motor units in the abductor pollicis brevis (an intrinsic thumb muscle) is associated with pinch-grip strength after controlling for sex and body weight (35). Additionally, Drey and colleagues have reported that the estimated number of functioning motor units in sarcopenic older adults lies roughly between the average of those observed in healthy persons and that observed in patients with the motor neuronal degenerative disease ALS (36). This finding suggests that in sarcopenic older adults, motor neuronal loss is particularly pronounced.

Neuromuscular Junction Transmission Failure and Sarcopenia

As the final nexus between the neurological and skeletal muscle systems, the integrity and function of the NMJ are necessary for dependable neural control of muscle force generation. The physiological role of the NMJ is to transmit action potentials from the nervous system to muscle fibers via the release of acetylcholine from the nerve terminal leading to the activation of nicotinic acetylcholine receptors in the opposing muscle fiber and, subsequently, the formation of a local synaptic potential in the endplate region of the muscle fiber (endplate potential). In the healthy state, the endplate potential is considerably greater than that required to complete neuromuscular transmission by triggering a muscle fiber action potential, but in numerous diseases, the endplate potentials are insufficient to excite the muscle fiber and this transmission failure contributes to weakness and fatigue.

There are several pieces of evidence suggestive of NMJ transmission failure with advancing age. For instance, markedly lower muscle force generation following peripheral nerve stimulation has been observed in comparison to direct muscle stimulation in the diaphragms of aged rats (37). Additionally, studies using stimulated single-fiber electromyography (SFEMG), which uses a selective recording electrode to directly assess muscle fiber AP generation in vivo, have reported that aged rodents exhibit notable amounts of NMJ transmission failure (38,39). This preclinical data are consistent with more indirect findings in humans that also suggests NMJ transmission failure is more pronounced in older versus younger adults (40). Together, these clinical and preclinical data provide a rationale for further exploring NMJ transmission as a function-promoting therapeutic strategy in older adults.

Research Gaps and Recommendations for Future Work

The neurological as well as muscular mechanisms that contribute to sarcopenia are incompletely understood. In particular, most data related to the neural mechanisms of sarcopenia fall within the lower half of the hierarchy of scientific evidence (Figure 4). These data are derived mainly from animal studies or cross-sectional human studies that simply compare younger versus older adults. Few are case–control studies that attempt to map physiological findings to negative health phenotypes, such as sarcopenia and/or frailty, and even fewer are longitudinal cohort studies. There have not been any rigorous clinical trials investigating the potential clinical utility of a neurotherapeutic compound for enhancing sarcopenia-related outcomes. However, there is some evidence for a variety of non-pharmacologic and pharmacologic approaches that used stimulants to enhance motor/muscle/physical function in older adults (see (41) for further details). For instance, a small trial (n = 18) reported that 3 weeks of L-DOPA administration resulted in notable improvements in both single- and dual-task gait speed (16% and 28%, respectively) in older adults with depression (42). With this said, there are growing calls to recognize the dangers of polypharmacy and the case for deprescribing in older adults (43). In particular, anticholinergics, benzodiazepines, antipsychotics, and opioids, all of which have sedative properties, are linked to adverse effects in older adults (43). Thus, a “less is more” pharmaceutical approach may be the most beneficial approach to enhancing physical function in older adults.

Conclusion

Neural mechanisms contribute, in part, to age-related weakness and mobility limitations. The fact that muscles are, conceptually, puppets of the nervous system likely explains why many anabolic therapies have not been shown to enhance physical function. The neurophysiological mechanisms of weakness are multifactorial, but likely include (a) supraspinal changes that are potentially linked to reduced cortical excitability, dopaminergic dysfunction, and arousal; (b) spinal changes that are potentially linked to loss of functioning motor units, reduced intrinsic motor neuron excitability (eg, reduced neuromodulation by the monoamines serotonin and norepinephrine), and slowed motor neuron firing rates; and (c) NMJ transmission failure. Further research is needed to determine the clinical relevance of physiological changes, map putative neural mechanisms to negative health phenotypes (eg, sarcopenia), and examine the effectiveness of various neurotherapeutic approaches to enhance physical function.

Funding

The work presented in this article was supported, in part, by grants from the National Institutes of Health (NIA R01AG067758, NIA R01AG044424, and NICHD R15HD065552) and NMD Pharma.

This supplement is sponsored by the National Institute on Aging (NIA) at the National Institutes of Health (NIH).

Conflict of Interest

In the past 5 years, Brian Clark has received research funding from NMD Pharma, Regeneron Pharmaceuticals, Astellas Pharma Global Development, Inc., and RTI Health Solutions for contracted studies that involved aging and muscle related research. In the past 5 years, Brian Clark has received consulting fees from Regeneron Pharmaceuticals, Zev industries, and the Gerson Lehrman Group for consultation specific to age-related muscle weakness. Brian Clark is a co-founder with equity of OsteoDx Inc.

References