Is There An Affiliation Between Low Skeletal Muscle Mass & Cognitive Perform?


Dementia is a significant public well being precedence. International prevalence signifies that over 55 million individuals worldwide live with dementia, with projections exhibiting that this quantity will attain ~140 million by 2050(1).

Studies indicated that as much as 40% of dementia circumstances are attributable to modifiable danger elements,

together with sarcopenia.

The prevalence of

sarcopenia in older community-dwelling people with dementia is greater than thrice increased than people with out dementia.  Provided that the present lack of medicines that may successfully forestall or reverse cognitive decline, it’s essential to establish modifiable risk-factors for cognitive decline.

Sarcopenia is a situation characterised by a progressive and generalized lack of muscle mass and performance.

It’s related to elevated danger of morbidity, useful impairment, and mortality. Sarcopenia is linked with cognitive decline(2), whereby sarcopenia markers, resembling weak grip energy and gradual gait pace, are predictors of cognitive perform and


The presumed organic mechanisms by which sarcopenia is related to cognitive decline are usually not fully understood.

Skeletal muscle is acknowledged as an vital endocrine organ that

releases myokines resembling brain-derived neurotrophic issue and interleukins

when it contracts(4)

Myokines have quite a few results and play a major position in multi-organ physiology and regulation, together with mind tissue(4).

Lack of muscle mass and performance (e.g., muscle weak point, mobility impairment) are additionally related to increased ranges of inflammatory, oxidative stress, and vascular points (e.g., microvascular dysfunction)(5) every of that are related to cognitive decline. Briefly, diminished mobility as a consequence of sarcopenia can doubtlessly contribute to diminished bodily exercise ranges and scale back socialization.

Low bodily exercise and social isolation are every vital danger elements for cognitive decline.

Analysis signifies that males who’ve decrements in muscle mass over a 4-year interval skilled considerably higher declines in international cognitive perform in contrast with

their male friends who maintained muscle mass(6). As well as, proof reveals that these with sarcopenia have a 2.4 instances higher danger of incident dementia(7).

4 Mechanisms explaining affiliation between low muscle mass and cognitive perform

Fig: Overview of the purported pathophysiological mechanisms explaining the affiliation between sarcopenia and

cognitive perform(8).

1. Systemic Irritation

Low skeletal muscle mass in older adults is related to low-grade,

systemic irritation, which in flip is related to cognitive impairment and dementia(9).

Proinflammatory cytokines originating from adipose (fats) tissue are increased in sedentary older people who show impaired muscle energy and energy in contrast with bodily energetic people. There’s a constructive affiliation with dementia and elevated concentrations of inflammatory markers resembling C-reactive protein, IL-6, and moore within the systemic circulation(10).

As talked about above, contracting skeletal muscle behaves like an endocrine organ secreting cytokines and peptides, referred to as myokines.

Muscle atrophy and the lack of kind II fibers, and subsequent swap to kind I fibers might lead to altered secretions of myokines. Myokines will be each pro- and anti inflammatory and embrace IL-6, IL-8, IL-15, and brain-derived neurotrophic issue. In accordance with the “Myokine Idea,” bodily inactive muscle groups repress their endocrine perform, which assists irritation and subsequently enhances the danger of dementia(11).

2. Insulin Metabolism

Skeletal muscle performs an vital position in glucose homeostasis as a result of it’s the dominant tissue chargeable for glucose storage and metabolism.

Low skeletal muscle mass is related to insulin resistance, and insulin resistance is an impartial danger issue for cognitive decline. Impaired glucose tolerance typically accompanies

insulin resistance with ageing(8).

Each glucose and insulin cross the blood-brain barrier and have intracerebral results, resembling synaptic transforming, regulating the expression of neurotransmitters, and performing selectively in mind areas to extend glucose metabolism. Hyperinsulinemia downregulates the quantity of insulin receptors within the blood-brain barrier and attenuates insulin transport within the mind. Ultimately, power hyperinsulinemia dampens tissue sensitivity to insulin, resulting in cerebrovascular injury(12).

Lengthy-term publicity to elevated concentrations of glucose leads to inappropriate secretion of insulin resulting in hyperinsulinemia, which negatively impacts neurons. Each utilization and uptake of glucose are impaired in Alzheimer’s illness. Peripheral insulin resistance results in hyperinsulinemia and impacts insulin signaling within 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 elevated muscle protein breakdown, which culminates in a detrimental web protein stability.

Decreased skeletal muscle protein synthesis that comes with ageing is known as “anabolic resistance”.  Low muscle mass ensuing from detrimental web protein stability may additionally replicate decrease protein concentrations within the mind, not directly affecting cognition.

Irregular depositions of misfolded and aggregated proteins are frequent in a number of forms of dementia(14).  One other possible mechanism linking low skeletal muscle mass with cognition is that low skeletal muscle mass is expounded to the upregulation of the ubiquitin-dependent proteolytic system, which is a significant pathway that clears short-lived, broken, and misfolded nuclear and cytoplasmic proteins and is upregulated in Alzheimer’s illness(15).   

The ubiquitin-proteasome system is expounded to the degradation of proteins and performs a vital position in neuronal signaling resembling synaptic exercise and neurotransmitter launch. A key determinant in Alzheimer’s illness pathophysiology is amyloid precursor protein, an acute-phase protein that’s depicted to be linked with the ubiquitin-dependent proteolytic system. The urged pathway is that dysfunction or overload of the ubiquitin-proteasome system might trigger accumulation of amyloid beta in

Alzheimer’s illness(15).

4. Mitochondrial Perform

The energetic wants for skeletal muscle contraction are offered by ATP, which is especially pushed by mitochondrial oxidative phosphorylation.

Skeletal muscle mitochondria fulfill completely different roles relating to metabolic regulation, that’s, apoptosis, synthesis, and catabolism of metabolites, and manufacturing and discount of reactive oxygen species(16).

Skeletal muscle groups use oxygen and in flip, produce giant quantities of reactive oxygen and nitrogen species. Beneath regular situations, reactive oxygen species are molecular sign transducers; nevertheless, overproduction of reactive oxygen species in dysfunctional mitochondria can result in

elevated oxidative stress and injury to organelles(17).

One frequent pathogenic mechanism of each sarcopenia and dementia is the involvement of oxidative stress, which is described because the imbalance between the technology of, and cleansing of reactive oxygen and nitrogen species in cells(17).

One potential pathophysiological mechanism brought on by impaired mitochondrial perform is known as “the oxidative stress principle,” in response to which accumulation of reactive oxygen and nitrogen species presumably results in mobile ageing(17).

Mitochondrial abnormalities (content material, perform, morphology) are frequent in people with low muscle mass. Mitochondrial dysfunction within the mind can be a doubtlessly underlying mechanism in dementia(18).

Interaction Between the 4 Mechanisms

There may be interaction between the 4 mechanisms talked about above. It’s believable that altered myokine launch from skeletal muscle are the important thing modulators of the 4 physiological hallmarks which might be related to cognitive decline. Myokines crosstalk with different molecular gamers within the mind to exert constructive results on neurogenesis, nervous system growth, and neuroprotection in response to train. 

Subsequently, bodily inactivity or a sedentary life-style lead to diminished launch of myokines, but additionally contributes to manufacturing of proinflammatory cytokines.

An vital age-related alteration of the neuromuscular system is the lower within the variety of motor items.

Motor items are the are the motor neuron and the muscle fibers it innervates. The amount of myokines could also be diminished as a consequence of low ranges of bodily exercise, which doubtlessly influences the lack of motor items that accompanies ageing, thereby influencing the pathways of curiosity (irritation, insulin metabolism, and mitochondria) within the mind microenvironment, through alterations to their paracrine and endocrine signaling.

The important thing takeaway is that the described mechanisms might result in a detrimental spiral, wherein cognitive impairment might additional exacerbate the loss in muscle mass and vice versa, and due to this fact, reverse causation can’t be excluded.


bodily train has a constructive affect on cognitive perform by growing synaptic plasticity and the underlying techniques that assist neurogenesis.  Medical implications relating to myokines are that they cross the blood-brain barrier, doubtlessly making them a goal for remedy as they affect the mind microenvironment. Recognizing the underlying pathophysiological mechanisms of muscle mass with cognition is vital to realize perception into dementia in addition to into the event of focused interventions.


Low skeletal muscle mass and alterations in myokine secretion led to irritation and decrease peripheral glucose storage as a consequence of low muscle mass. These are the primary mechanisms with probably the most proof that explains the affiliation with impaired cognition.

Skeletal muscle in an indicator of well being and a worthwhile “useful resource” to mitigate the lack of high quality of life. Additionally it is very clear the worth skeletal muscle has on our well being, each bodily and cognitively.

I believe the understanding of the muscle-brain connection remains to be in its infancy. There will likely be rather more work popping out sooner or later delineating the mechanisms on how muscle preserves and mitigates mind ageing.  

Along with resistance coaching, hydration, sleep, and maitaining adequate protein consumption, top-of-the-line methods to assist your physique keep muscle mass is to complement with creatine on daily basis. Not solely is it probably the most researched complement on the planet in relation to muscle and energy, rising analysis suggests it has huge ranging results on mind well being too.

You possibly can be taught extra about creatine and mind well being

right here.


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    3.    Greatest JR, Liu-Ambrose T, Boudreau RM, et al: An Analysis of the Longitudinal, Bidirectional Associations Between Gait Pace and Cognition in Older Girls and Males. J Gerontol A Biol Sci Med Sci 71:1616-1623, 2016
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    6.    Uchida Ok, Sugimoto T, Tange C, et al: Affiliation between Discount of Muscle Mass and Quicker Declines in International Cognition amongst Older Individuals: A 4-Yr Potential Cohort Examine. J Nutr Well being Growing older 27:932-939, 2023
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    8.    Oudbier SJ, Goh J, Looijaard S, et al: Pathophysiological Mechanisms Explaining the Affiliation Between Low Skeletal Muscle Mass and Cognitive Perform. J Gerontol A Biol Sci Med Sci 77:1959-1968, 2022
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