Pathophysiological Mechanisms Explaining the Association Between Low Skeletal Muscle Mass and Cognitive Function

Abstract

Low skeletal muscle mass is associated with cognitive impairment and dementia in older adults. This review describes the possible underlying pathophysiological mechanisms: systemic inflammation, insulin metabolism, protein metabolism and mitochondrial function. We hypothesize that the central tenet in this pathophysiology is the dysfunctional myokine secretion consequent to minimal physical activity. Myokines, such as fibronectin type III domain containing 5/irisin and cathepsin B are released by physically active muscle and cross the blood-brain-barrier. These myokines upregulate local neurotrophin expression such as brain-derived neurotrophic factor (BDNF) in the brain microenvironment. BDNF exerts anti-inflammatory effects that may be responsible for neuroprotection. Altered myokine secretion due to physical inactivity exacerbates inflammation and impairs muscle glucose metabolism, potentially affecting the transport of insulin across the blood-brain barrier. Our working model also suggests other underlying mechanisms. A negative systemic protein balance, commonly observed in older adults, contributes to low skeletal muscle mass and may also reflect deficient protein metabolism in brain tissues. As a result of age-related loss in skeletal muscle mass, decrease in the abundance of mitochondria and detriments in their function, lead to a decrease in tissue oxidative capacity. Dysfunctional mitochondria in skeletal muscle and brain result in the excessive production of reactive oxygen species, which drives tissue oxidative stress and further perpetuates the dysfunction in mitochondria. Both oxidative stress and accumulation of mitochondrial DNA mutations due to aging drive cellular senescence. A targeted approach in the pathophysiology of low muscle mass and cognition could be to restore myokine balance by physical activity.

An examination of the relationship among plasma brain derived neurotropic factor, peripheral vascular function, and body composition with cognition in midlife African Americans/Black individuals

“…The results of Csipo et al (2019) have supported this by indicating that vascular-related risk factors predicted cognitive dysfunction in older adults [ n = 29 (28, White)]. This relationship is suspected to be multifaceted, but an overall consequence of aging includes the disruption to the blood brain barrier ( Chernick et al, 2019 ; Nation et al, 2019 ; Montagne et al, 2020 ; Pluvinage and Wyss-Coray, 2020 ; Nelson, 2022 ; Oudbier et al, 2022 ), which may be exacerbated by increased peripheral arterial stiffness and endothelial dysfunction ( Winder et al, 2021 ; Bailey et al, 2022 ). Furthermore, a product of peripheral vascular dysfunction includes the attenuation of BDNF production considering that, as previously mentioned, BDNF is produced by the hippocampus as well as non-neuronal tissues such as vascular endothelial cells ( Nakahashi et al, 2000 ; Lemos et al, 2016 ).…”

“…Outside of the central nervous system (e.g., glia cells and neurons), BDNF is commonly reported to be released from skeletal and vascular smooth muscle cells as well as endothelial cells ( Jodeiri Farshbaf and Alviña, 2021 ). In fact, a reduction in BDNF release from these cells is one of the hallmark physiological changes seen in neurodegenerative disorders, including AD ( Ismail et al, 2020 ; Lourenco et al, 2020 ; Huuha et al, 2022 ; Oudbier et al, 2022 ). Increases in BDNF, however, are a hypothesized mediating pathway of cognitive enhancement following habitual and acute physical activity ( Anderson-Hanley et al, 2012 ; Babaei et al, 2014 ; Fortune et al, 2019 ; Walsh et al, 2020 ; Ruiz-González et al, 2021 ; Umegaki et al, 2021 ).…”

“…Peripheral organ health is a key factor in terms of influencing overall brain health and function ( Pluvinage and Wyss-Coray, 2020 ; Winder et al, 2021 ; Huuha et al, 2022 ; Nelson, 2022 ; Oudbier et al, 2022 ; Saiyasit et al, 2022 ). In particular, numerous studies have demonstrated the importance of peripheral vascular health as it relates to the maintenance of cognitive function and prevention of neurodegeneration ( Csipo et al, 2019 ; Albrecht et al, 2020 ; Winder et al, 2021 ; Bailey et al, 2022 ; Nelson, 2022 ; Saiyasit et al, 2022 ), especially given the continued increase in prevalence of modifiable risk factors like obesity that (in)directly affect vascular function ( Kim and Kim, 2021 ; Koenen et al, 2021 ).…”

“…There is a persisting need to determine the best practice for improving/maintaining various tissues (adipose vs. lean tissue) across the lifespan. Several mechanisms link body composition to neurodegeneration ( Gilder et al, 2014 ; Kaur et al, 2016 ; Jyväkorpi et al, 2020 ; Whitaker et al, 2021 ), and it has even been suggested that lean mass may be more related to cognitive outcomes than adipose tissue ( Burns et al, 2010 ; Taekema et al, 2012 ; Spahillari et al, 2016 ; Mereu et al, 2018 ; Oudbier et al, 2022 ). It has been proposed that the link between lean mass and cognition includes myokine secretion (e.g., BDNF), insulin resistance, oxidative stress, and mitochondrial dysfunction ( Oudbier et al, 2022 ).…”

“…Several mechanisms link body composition to neurodegeneration ( Gilder et al, 2014 ; Kaur et al, 2016 ; Jyväkorpi et al, 2020 ; Whitaker et al, 2021 ), and it has even been suggested that lean mass may be more related to cognitive outcomes than adipose tissue ( Burns et al, 2010 ; Taekema et al, 2012 ; Spahillari et al, 2016 ; Mereu et al, 2018 ; Oudbier et al, 2022 ). It has been proposed that the link between lean mass and cognition includes myokine secretion (e.g., BDNF), insulin resistance, oxidative stress, and mitochondrial dysfunction ( Oudbier et al, 2022 ). Further, recent findings indicated that Finnish adults with more favorable body composition (e.g., higher skeletal muscle mass) at midlife were associated with increased odds of reaching 90 years of age as well as higher quality of life scores at age 73 ( Whitaker et al, 2021 ).…”