Is There An Association Between Low Skeletal Muscle Mass and Cognitive Function?
The term 'meathead' has often been used in a derogatory manner. Turns out, having more muscle may be better for the brain. But just how important is it? In this article, Dr. Paul Henning looks at the association between cognitive function and low muscle mass as you age.More
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Dementia is a major public health priority. Global prevalence indicates that over 55 million people worldwide are living with dementia, with projections showing that this number will reach ~140 million by 2050(1).
Reports indicated that up to 40% of dementia cases are attributable to modifiable risk factors, including sarcopenia.
The prevalence of sarcopenia in older community-dwelling individuals with dementia is more than three times higher than individuals without dementia. Given that the current lack of medications that can effectively prevent or reverse cognitive decline, it is crucial to identify modifiable risk-factors for cognitive decline.
Sarcopenia is a condition characterized by a progressive and generalized loss of muscle mass and function.
It is associated with increased risk of morbidity, functional impairment, and mortality. Sarcopenia is linked with cognitive decline(2), whereby sarcopenia markers, such as weak grip strength and slow gait speed, are predictors of cognitive function and dementia(3).
The presumed biological mechanisms by which sarcopenia is associated with cognitive decline are not completely understood.
Skeletal muscle is recognized as an important endocrine organ that releases myokines such as brain-derived neurotrophic factor and interleukins when it contracts(4).
Myokines have numerous effects and play a significant role in multi-organ physiology and regulation, including brain tissue(4).
Loss of muscle mass and function (e.g., muscle weakness, mobility impairment) are also associated with higher levels of inflammatory, oxidative stress, and vascular issues (e.g., microvascular dysfunction)(5) each of which are associated with cognitive decline. Briefly, reduced mobility due to sarcopenia can potentially contribute to reduced physical activity levels and reduce socialization.
Low physical activity and social isolation are each important risk factors for cognitive decline.
Research indicates that males who have decrements in muscle mass over a 4-year period experienced significantly greater declines in global cognitive function compared with their male peers who maintained muscle mass(6). In addition, evidence shows that those with sarcopenia have a 2.4 times greater risk of incident dementia(7).
4 Mechanisms explaining association between low muscle mass and cognitive function
Fig: Overview of the purported pathophysiological mechanisms explaining the association between sarcopenia and cognitive function(8).
1. Systemic Inflammation
Low skeletal muscle mass in older adults is associated with low-grade, systemic inflammation, which in turn is associated with cognitive impairment and dementia(9).
Proinflammatory cytokines originating from adipose (fat) tissue are higher in sedentary older individuals who demonstrate impaired muscle strength and power compared with physically active individuals. There is a positive association with dementia and elevated concentrations of inflammatory markers such as C-reactive protein, IL-6, and moore in the systemic circulation(10).
As mentioned above, contracting skeletal muscle behaves like an endocrine organ secreting cytokines and peptides, called myokines.
Muscle atrophy and the loss of type II fibers, and subsequent switch to type I fibers may result in altered secretions of myokines. Myokines can be both pro- and anti-inflammatory and include IL-6, IL-8, IL-15, and brain-derived neurotrophic factor. According to the “Myokine Concept,” physically inactive muscles repress their endocrine function, which assists inflammation and subsequently enhances the risk of dementia(11).
2. Insulin Metabolism
Skeletal muscle plays an important role in glucose homeostasis because it is the dominant tissue responsible for glucose storage and metabolism.
Low skeletal muscle mass is associated with insulin resistance, and insulin resistance is an independent risk factor for cognitive decline. Impaired glucose tolerance often accompanies insulin resistance with aging(8).
Both glucose and insulin pass the blood-brain barrier and have intracerebral effects, such as synaptic remodeling, regulating the expression of neurotransmitters, and acting selectively in brain regions to increase glucose metabolism. Hyperinsulinemia downregulates the amount of insulin receptors in the blood-brain barrier and attenuates insulin transport in the brain. Eventually, chronic hyperinsulinemia dampens tissue sensitivity to insulin, leading to cerebrovascular damage(12). Long-term exposure to elevated concentrations of glucose results in inappropriate secretion of insulin leading to hyperinsulinemia, which negatively affects neurons. Both utilization and uptake of glucose are impaired in Alzheimer’s disease. Peripheral insulin resistance leads to hyperinsulinemia and affects insulin signaling in the central nervous system, consequently stimulating tau phosphorylation, oxidative stress, and toxicity of amyloid beta, which promotes cognitive decline(13).
3. Protein Metabolism
Skeletal muscle mass is negatively affected by decreased muscle protein synthesis and increased muscle protein breakdown, which culminates in a negative net protein balance.
Decreased skeletal muscle protein synthesis that comes with aging is called “anabolic resistance”. Low muscle mass resulting from negative net protein balance could also reflect lower protein concentrations in the brain, indirectly affecting cognition.
Abnormal depositions of misfolded and aggregated proteins are common in several types of dementia(14). Another probable mechanism linking low skeletal muscle mass with cognition is that low skeletal muscle mass is related to the upregulation of the ubiquitin-dependent proteolytic system, which is a major pathway that clears short-lived, damaged, and misfolded nuclear and cytoplasmic proteins and is upregulated in Alzheimer’s disease(15). The ubiquitin-proteasome system is related to the degradation of proteins and plays an essential role in neuronal signaling such as synaptic activity and neurotransmitter release. A key determinant in Alzheimer’s disease pathophysiology is amyloid precursor protein, an acute-phase protein that is depicted to be connected with the ubiquitin-dependent proteolytic system. The suggested pathway is that dysfunction or overload of the ubiquitin-proteasome system may cause accumulation of amyloid beta in Alzheimer’s disease(15).
4. Mitochondrial Function
The energetic needs for skeletal muscle contraction are provided by ATP, which is mainly driven by mitochondrial oxidative phosphorylation.
Skeletal muscle mitochondria fulfill different roles regarding metabolic regulation, that is, apoptosis, synthesis, and catabolism of metabolites, and production and reduction of reactive oxygen species(16).
Skeletal muscles use oxygen and in turn, produce large amounts of reactive oxygen and nitrogen species. Under normal conditions, reactive oxygen species are molecular signal transducers; however, overproduction of reactive oxygen species in dysfunctional mitochondria can lead to increased oxidative stress and damage to organelles(17).
One common pathogenic mechanism of both sarcopenia and dementia is the involvement of oxidative stress, which is described as the imbalance between the generation of, and detoxification of reactive oxygen and nitrogen species in cells(17). One potential pathophysiological mechanism caused by impaired mitochondrial function is called “the oxidative stress theory,” according to which accumulation of reactive oxygen and nitrogen species possibly leads to cellular aging(17). Mitochondrial abnormalities (content, function, morphology) are common in individuals with low muscle mass. Mitochondrial dysfunction in the brain is also a potentially underlying mechanism in dementia(18).
Interplay Between the 4 Mechanisms
There is interplay between the four mechanisms mentioned above. It is plausible that altered myokine release from skeletal muscle are the key modulators of the four physiological hallmarks that are associated with cognitive decline. Myokines crosstalk with other molecular players in the brain to exert positive effects on neurogenesis, nervous system development, and neuroprotection in response to exercise.
Therefore, physical inactivity or a sedentary lifestyle result in reduced release of myokines, but also contributes to production of proinflammatory cytokines.
An important age-related alteration of the neuromuscular system is the decrease in the number of motor units.
Motor units are the are the motor neuron and the muscle fibers it innervates. The quantity of myokines may be reduced due to low levels of physical activity, which potentially influences the loss of motor units that accompanies aging, thereby influencing the pathways of interest (inflammation, insulin metabolism, and mitochondria) in the brain microenvironment, via alterations to their paracrine and endocrine signaling.The key takeaway is that the described mechanisms may lead to a negative spiral, in which cognitive impairment may further exacerbate the loss in muscle mass and vice versa, and therefore, reverse causation cannot be excluded.In general, physical exercise has a positive influence on cognitive function by increasing synaptic plasticity and the underlying systems that support neurogenesis. Clinical implications regarding myokines are that they cross the blood-brain barrier, potentially making them a target for therapy as they influence the brain microenvironment. Recognizing the underlying pathophysiological mechanisms of muscle mass with cognition is important to gain insight into dementia as well as into the development of targeted interventions.
Summary
Low skeletal muscle mass and alterations in myokine secretion led to inflammation and lower peripheral glucose storage due to low muscle mass. These are the main mechanisms with the most evidence that explains the association with impaired cognition.
Skeletal muscle in an indicator of health and a valuable “resource” to mitigate the loss of quality of life. It is also very clear the value skeletal muscle has on our health, both physically and cognitively.
I think the understanding of the muscle-brain connection is still in its infancy. There will be much more work coming out in the future delineating the mechanisms on how muscle preserves and mitigates brain aging.
In addition to resistance training, hydration, sleep, and maitaining sufficient protein consumption, one of the best ways to help your body maintain muscle mass is to supplement with creatine every day. Not only is it the most researched supplement on the planet when it comes to muscle and strength, emerging research suggests it has wide ranging effects on brain health too.
You can learn more about creatine and brain health here.
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