Editorial: Bidirectional Communication Between Brain and Muscle.

J Nutr Health Aging. 2018;22(10):1144-1145. doi: 10.1007/s12603-018-1141-2.

“What we have here is a failure to communicate.”

Cool Hand Luke

Communication between the brain and muscle plays a key role in maintaining the function of an individual. A classical example of this failure to communicate is after a stroke which leads to a failure of the brain to communicate with the periphery resulting in the muscle becoming flaccid. With aging there is a gradual decline in the communication between the central nervous system and skeletal muscle. This leads to a decrease in speed of movement, weakness, an increased tendency to fall and eventually a decline in function.

A number of studies have shown that deterioration in brain function leads to a decline in grip strength and walking speed. For example, older persons with the lowest MiniMental Status Examination score and poor verbal ability had lower grip strength (1). Ten percent variance in gait speed is due to the amyloid-beta burden in the brain together with the presence of the apolipoprotein E4 gene (2). A classical example of the brain-muscle communication decrease with aging is the decline in the ability of old persons with dementia or Parkinson’s disease to “dual task.” (3) “Dual tasking” deficit is the inability to maintain walking speed while being asked to carry out a mental task. Both children up to 12 and older persons have a decrease in walking speed when asked to do an arithmetic problem.

With aging there is a decrease in axonal communication leading to a decline in the connection between the cortex and the spinal cord (4). The decline in dopamine receptors with aging results in slowed reaction times (5). With aging there is a decrease in motor unit numbers leading to fiber size heterogeneity and fiber grouping similar to the changes seen in amyotrophic lateral sclerosis and a loss of type 2 muscle fibers (6). When this is pronounced, it results in sarcopenia. In addition, the increase in adenosine (A1) inhibitory receptors over the adenosine 2A receptors results in decreased muscle force (7).

From Muscle to Brain

“Methinks that the moment my legs begin to move, My thoughts begin to flow”

～Henry David Thoreau, 1851

Physical exercise increases hippocampal volume in older persons (8). In persons with mild cognitive impairment there is an increase in brain activation after 12 weeks of training (9). Exercise increases mental performance and function in older persons (10-13). Overall, exercise increases neurogenesis, neuronal maturation, angiogenesis, hippocampal volume and learning and memory in mice (14). Exercise directly increases BDNF, APP and BACE-1 in Alzheimer’s disease rat brain (15).

For muscle to produce these effects it produces a variety of myokines that have a direct effect on the brain (16). Among these myokines the ones that have been shown to have effects on the central nervous system include insulin-growth factor-1, brain derived nerve growth factor, cathepsin-B, fibroblast growth factor-1 and irisin (17). Irisin has been considered a major peptide communicator (18), but recently studies have suggested that the assays that have been used are very nonspecific (19, 20).

Another effect of muscle on the brain is to increase fatigue (21). Exercising muscle increases tryptophan and branched chain amino acids release in the blood leading to an increase in tryptophan in the brain (22, 23). In the brain tryptophan is converted into serotonin that inhibits neuronal activity leading to a sense of fatigue (24). Exercise also reverses depressive behaviors (25).

Cognitive Frailty

Cognitive frailty is defined as a person with reduced cognitive reserve associated with physical frailty (26, 27) (Figure 1). Persons with cognitive frailty have worse physical outcomes than persons who only have frailty (28-30).

Persons who have an increase in regional white matter burden (vascular disease) have increased balance and gait disorders, falls, urge incontinence, functional decline, and disability and worse executive function (31-33). Besides the role of vascular disease producing cognitive frailty, another causative factor is inflammatory cytokines. Inflammatory cytokines are elevated in physical frailty (34). The cytokines can cross the blood brain barrier leading to impaired cognition (35).

Motoric Cognitive Risk Syndrome is similar to cognitive frailty (36). It is defined as an older person with slow gait and memory complaints, without dementia. Its pathophysiology is considered to be due to decreased gray matter volume and hippocampal volume together with an increase in white matter hyperintensities.

Conclusion

A failure to communicate between brain-muscle-brain plays a significant role in the aging process. This failure leads to frailty, sarcopenia, fatigue, depression and cognitive frailty

References available on pubmed