Pathogenesis of sarcopenia and the relationship with fat mass: descriptive review

May combine two claims.

Assuming adipocyte dysfunction is the first of many drivers of local inflammation and insulin resistance (IR), followed by a vicious cycle (the metabaging cycle) that spreads systemically, may be the best unifying explanation for the metabolic syndrome that causes both obesity and sarcopenia during ageing, and further explains the obesity paradox in certain age groups.

“Our review posits that assuming adipocyte dysfunction is the first of many drivers of local inflammation and insulin resistance (IR), followed by a vicious cycle (the metabaging cycle) that spreads systemically, may be the best unifying explanation for the metabolic syndrome that causes both obesity and sarcopenia during ageing, and further explains the obesity paradox in certain age groups.”

• AssumptionThe authors state this as an assumption: Adipocyte dysfunction is the first of many drivers of local inflammation and insulin resistance.

May combine two claims.

Studies increasingly recognize the importance of muscular fatty infiltrations for the age-mediated loss of skeletal muscle function, and suggest that this factor is closely linked to physical inactivity.

“Studies have increasingly recognized the importance of muscular fatty infiltrations for the age‐mediated loss of skeletal muscle function, and are beginning to suggest that this new important factor is closely linked to physical inactivity.[ 18 ]”

• cites [18] Brioche T, Pagano AF, Py G, Chopard A. Muscle wasting and aging: experimental models, fatty infiltrations, and prevention. Mol Asp Med. 2016; 50: 56– 87. 27106402 sourceNot checked yet

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Loss of muscle leads to weakness, loss of independence, and increased risk of death.

“Loss of muscle has a serious consequence on many chronic diseases, and on ageing itself, because it leads to weakness, loss of independence, and increased risk of death.[ 4 ]”

• cites [4] Kob R, Fellner C, Bertsch T, Wittmann A, Mishura D, Sieber CC, et al. Gender‐specific differences in the development of sarcopenia in the rodent model of the ageing high‐fat rat. J Cachexia Sarcopenia Muscle. 2015; 6: 181– 191. 26136194 PMC4458084 sourceNot checked yet

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The extant adipocytes' impaired insulin signalling permits lipolysis, further promoting local hyperlipidaemia.

“Furthermore, the extant adipocytes' impaired insulin signalling permits lipolysis, further promoting local hyperlipidaemia.[ 28 ]”

• cites [28] Scherer PE. The multifaceted roles of adipose tissue‐therapeutic targets for diabetes and beyond: the 2015 Banting lecture. Diabetes. 2016; 65: 1452– 1461. 27222389 PMC4878420 sourceNot checked yet

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Classified as probably not a substantial claim. May combine two claims.

Studies were excluded if they concerned non-sarcopenia-relevant basic research, neuromuscular junction mechanism and gut microbiota mechanisms, or if subjects were young adults.

“Studies were excluded if (1) study topic: non‐sarcopenia‐relevant basic research, neuromuscular junction mechanism and gut microbiota mechanisms; (2) subjects: young adults.”

May combine two claims.

Sarcopenic muscles show reduced numbers of stem cells (called satellite cells) and terminally differentiated myofibres.

“Sarcopenic muscles show reduced numbers of stem cells (called satellite cells) and terminally differentiated myofibres.”

• cites [7] Verdijk LB, Snijders T, Drost M, Delhaas T, Kadi F, Loon LJCV. Satellite cells in human skeletal muscle; from birth to old age. Age (Dordr). 2014; 36: 545– 547. 24122288 PMC4039250 sourceNot checked yet

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The proportions of visceral fat and intramuscular fat increase with age, reaching a peak between 60 and 75 years old, as the proportion of subcutaneous fat decreases.

“The proportions of visceral fat and intramuscular fat also increase with age, reaching a peak between 60 and 75 years old, as the proportion of subcutaneous fat decreases.[ 9 ]”

• cites [9] Stenholm S, Harris TB, Rantanen T, Visser M, Kritchevsky SB, Ferrucci L. Sarcopenic obesity: definition, cause and consequences. Curr Opin Clin Nutr Metab Care. 2008; 11: 693– 700. 18827572 PMC2633408 sourceNot checked yet

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The expansion of adipose depots can be driven either by the increase in adipocyte size (hypertrophy), or by the formation of new adipocytes from perivascular preadipocytes and pericytes (hyperplasia).

“The expansion of adipose depots can be driven either by the increase in adipocyte size (hypertrophy), or by the formation of new adipocytes from perivascular preadipocytes and pericytes (hyperplasia).[ 23 ]”

• cites [23] Ghaben AL, Scherer PE. Adipogenesis and metabolic health. Nat Rev Mol Cell Biol. 2019; 20: 242– 258. 30610207 sourceNot checked yet

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Fatty infiltration into both muscle and bone, and the redistribution of subcutaneous fat to the intra-abdominal area (visceral fat), all result in decreased overall strength and functionality, increasing the risk of falls and fractures, and a potential increase in morbidity.

“Fatty infiltration into both muscle and bone, and the redistribution of subcutaneous fat to the intra‐abdominal area (visceral fat), all result in decreased overall strength and functionality, increasing the risk of falls and fractures, and a potential increase in morbidity.[ 8 ]”

• cites [8] Cruz‐Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, et al. Sarcopenia: European consensus on definition and diagnosis: report of the European Working Group on Sarcopenia in Older People. Age Ageing. 2010; 39: 412– 423. 20392703 PMC2886201 sourceNot checked yet

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Patients with sarcopenic obesity (SO) show an increased risk of systemic insulin resistance, systemic inflammation, associated chronic diseases, and the subsequent progression to full-blown sarcopenia and even cachexia.

“Patients with SO show an increased risk of systemic insulin resistance, systemic inflammation, associated chronic diseases, and the subsequent progression to full‐blown sarcopenia and even cachexia.”

• cites [62] Scott D, Chandrasekara SD, Laslett LL, Cicuttini F, Ebeling PR, Jones G. Associations of Sarcopenic Obesity and Dynapenic Obesity with Bone Mineral Density and Incident Fractures Over 5‐10 Years in Community‐Dwelling Older Adults. Calcif Tissue Int. 2016; 99: 30– 42. 26939775 sourceNot checked yet

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Lipids and their derivatives accumulate both within and between muscle cells, inducing mitochondrial dysfunction, disturbing β-oxidation of fatty acids, and enhancing reactive oxygen species (ROS) production, leading to lipotoxicity and insulin resistance, as well as enhanced secretion of some pro-inflammatory cytokines.

“Lipids and their derivatives accumulate both within and between muscle cells, inducing mitochondrial dysfunction, disturbing β‐oxidation of fatty acids, and enhancing reactive oxygen species (ROS) production, leading to lipotoxicity and insulin resistance, as well as enhanced secretion of some pro‐inflammatory cytokines.”

Classified as probably not a substantial claim. May combine two claims.

Primary studies were included if they met the following criteria: animal research, clinical research and cell experiments; elderly persons and aged animals with sarcopenia or sarcopenic obesity; and primary indexes of muscle atrophy, ectopic fat infiltration, fat wasting, and decline of physical function.

“Primary studies were included if they met the following criteria: (1) study type: animal research, clinical research and cell experiments; (2) subjects: elderly persons and aged animals with sarcopenia or sarcopenic obesity; (3) primary indexes: muscle atrophy, ectopic fat infiltration, fat wasting, and decline of physical function.”

May combine two claims.

The redistribution of fat does not necessarily manifest as obesity, but intramuscular fat infiltration generally increases the chances of progression to obesity across adults.

“It is noteworthy that while the redistribution of fat does not necessarily manifest as obesity, intramuscular fat infiltration generally increases the chances of progression to obesity across adults.[ 11 ]”

• cites [11] Vivodtzev I, Moncharmont L, Tamisier R, Borel JC, Arbib F, Wuyam B, et al. Quadriceps muscle fat infiltration is associated with cardiometabolic risk in COPD. Clin Physiol Funct Imaging. 2018; 38: 788– 797. 29105276 sourceNot checked yet

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These molecular changes interact with each other, leading to a vicious cycle that impairs the regeneration of muscle and blocks the recovery of physical function.

“These molecular changes interact with each other, leading to a vicious cycle that impairs the regeneration of muscle and blocks the recovery of physical function.[ 16 ]”

• cites [16] Lipina C, Hundal HS. Lipid modulation of skeletal muscle mass and function. J Cachexia Sarcopenia Muscle. 2017; 8: 190– 201. 27897400 PMC5377414 sourceNot checked yet

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In nonagenarians, muscle fat infiltration is positively correlated with the area of pericardial and visceral adipose tissue, although visceral fat mass becomes protective against frailty in this age group.

“Interestingly, a major geriatric study of nonagenarians indicated that, muscle fat infiltration is still positively correlated with the area of pericardial and visceral adipose tissue in these oldest old individuals, although visceral fat mass strangely become protective against frailty in this age group (part of a phenomenon known as the obesity paradox, which we will address in a later section).”

• cites [10] Idoate F, Cadore EL, Casas‐Herrero A, Zambom‐Ferraresi F, Marcellan T, Gordoa AR, et al. Adipose tissue compartments, muscle mass, muscle fat infiltration, and coronary calcium in institutionalized frail nonagenarians. Eur Radiol. 2015; 25: 2163– 2175. 25510447 sourceNot checked yet

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ROS overproduction in myoblasts causes accumulation of S100B, which promote the myoblast-to-adipocyte transition, and myoblasts from sarcopenic subjects show properties of (pre)adipocytes.

“ROS overproduction in myoblasts causes accumulation of S100B, which promote the myoblast‐to‐adipocyte transition, and myoblasts from sarcopenic subjects show properties of (pre)adipocytes.[ 31 ]”

• cites [31] Morozzi G, Beccafico S, Bianchi R, Riuzzi F, Bellezza I, Giambanco I, et al. Oxidative stress‐induced S100B accumulation converts myoblasts into brown adipocytes via an NF‐κB/YY1/miR‐133 axis and NF‐κB/YY1/BMP‐7 axis. Cell Death Differ. 2017; 24: 2077– 2088. 28885620 PMC5686349 sourceNot checked yet

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May combine two claims.

Age-associated obesity and muscle atrophy (sarcopenia) are intimately connected and are reciprocally regulated by adipose tissue and skeletal muscle dysfunction.

“Age‐associated obesity and muscle atrophy (sarcopenia) are intimately connected and are reciprocally regulated by adipose tissue and skeletal muscle dysfunction.”

May combine two claims.

During ageing, adipose inflammation leads to the redistribution of fat to the intra-abdominal area (visceral fat) and fatty infiltrations in skeletal muscles, resulting in decreased overall strength and functionality.

“During ageing, adipose inflammation leads to the redistribution of fat to the intra‐abdominal area (visceral fat) and fatty infiltrations in skeletal muscles, resulting in decreased overall strength and functionality.”

May combine two claims.

Adipose tissue hypoxia either increases the expression of pro-fibrotic genes and leads to adipose fibrosis, or directly leads to adipose necrosis, inducing infiltration by immune cells and adipose inflammation.

“Adipose tissue hypoxia either increases the expression of pro‐fibrotic genes and leads to adipose fibrosis, or directly leads to adipose necrosis, inducing infiltration by immune cells and adipose inflammation.[ 25 ]”

• cites [25] Khan T, Muise ES, Iyengar P, Wang ZC, Chandalia M, Abate N, et al. Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol Cell Biol. 2009; 29: 1575– 1591. 19114551 PMC2648231 sourceNot checked yet

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Deposition of intramyocellular lipids promotes lipotoxicity, which induces and aggravates mitochondrial dysfunction, oxidative stress, insulin resistance (IR), and inflammation.

“Deposition of intramyocellular lipids further promotes lipotoxicity, which induces and aggravates mitochondrial dysfunction, oxidative stress, insulin resistance (IR), and inflammation.[ 15 ]”

• cites [15] D'Souza K, Mercer A, Mawhinney H, Pulinilkunnil T, Udenigwe CC, Kienesberger PC. Whey peptides stimulate differentiation and lipid metabolism in adipocytes and ameliorate lipotoxicity‐induced insulin resistance in muscle cells. Nutrients. 2020; 12: 425. PMC7071342 32041341 sourceNot checked yet

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In obesity, muscle progenitor cells could differentiate to an adipocyte-like phenotype as a result of paracrine signals from cytokines, leading to reduced muscular renewal, increased fatty infiltration, and thus a vicious cycle.

“In obesity, muscle progenitor cells could also differentiate to an adipocyte‐like phenotype as a result of paracrine signals from cytokines, leading to reduced muscular renewal, increased fatty infiltration, and thus a vicious cycle.[ 12 ]”

• cites [12] Kob R, Bollheimer LC, Bertsch T, Fellner C, Djukic M, Sieber CC, et al. Sarcopenic obesity: molecular clues to a better understanding of its pathogenesis? Biogerontology. 2015; 16: 15– 29. 25376109 sourceNot checked yet

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Type II glycolytic myofibres become hypotrophic with reduced diameter, and the muscles become infiltrated with adipose tissue and, at later stages, fibrotic tissue.

“Moreover, type II glycolytic myofibres become hypotrophic with reduced diameter, and the muscles become infiltrated with adipose tissue and, at later stages, fibrotic tissue.[ 7 ]”

• cites [7] Verdijk LB, Snijders T, Drost M, Delhaas T, Kadi F, Loon LJCV. Satellite cells in human skeletal muscle; from birth to old age. Age (Dordr). 2014; 36: 545– 547. 24122288 PMC4039250 sourceNot checked yet

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Classified as probably not a substantial claim.

A comprehensive literature search was performed on the PubMed, EMBASE, OVID, and Cochrane library databases, using data from 1 January 2015 to 31 June 2021.

“A comprehensive literature search was performed on the PubMed, EMBASE, OVID, and Cochrane library databases, using data from 1 January 2015 to 31 June 2021.”

May combine two claims.

Muscle-secreted cytokines may exacerbate adipose tissue atrophy, support chronic low-grade inflammation, and establish a vicious cycle of local hyperlipidaemia, insulin resistance, and inflammation that spreads systemically, thus promoting the development of sarcopenic obesity (SO).

“In turn, these muscle‐secreted cytokines may exacerbate adipose tissue atrophy, support chronic low‐grade inflammation, and establish a vicious cycle of local hyperlipidaemia, insulin resistance, and inflammation that spreads systemically, thus promoting the development of sarcopenic obesity (SO).”

May combine two claims.

Across populations today, muscle mass remains relatively stable during early life, but after age ~30 years, muscle mass declines at a rate of ~0.5-1.0% per year.

“Across populations today, muscle mass remains relatively stable during early life, but after age ~30 years, muscle mass declines at a rate of ~0.5–1.0% per year.[ 2 ]”

• cites [2] Kemmler W, Stengel SV, Schoene D. Longitudinal changes in muscle mass and function in older men at increased risk for sarcopenia—the FrOST‐Study. J Frailty Aging. 2019; 8: 57– 61. 30997916Not checked yet

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HSL and ATGL need to work in concert to regulate lipolysis in skeletal muscle, and their discordant activity are thought to be responsible for dysregulated lipolysis and IR in the skeletal muscle of obese and type II diabetes mellitus (T2DM) individuals.

“HSL and ATGL need to work in concert to regulate lipolysis in skeletal muscle, and their discordant activity are thought to be responsible for dysregulated lipolysis and IR in the skeletal muscle of obese and type II diabetes mellitus (T2DM) individuals.[ 51 ]”

• cites [51] Kase ET, Feng YZ, Badin PM, Bakke SS, Laurens C, Coue M, et al. Primary defects in lipolysis and insulin action in skeletal muscle cells from type 2 diabetic individuals. Biochim Biophys Acta. 2015; 1851: 1194– 1201. 25819461 sourceNot checked yet

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Ageing is linked to altered synthesis of nitric oxide (NO) in skeletal muscle, which regulates FAP fate through inhibition of their differentiation into adipocytes.

“Ageing is also linked to altered synthesis of nitric oxide (NO) in skeletal muscle,[ 47 ] which regulates FAP fate through inhibition of their differentiation into adipocytes.”

• cites [47] Samengo G, Avik A, Fedor B, Whittaker D, Myung KH, Wehling‐Henricks M, et al. Age‐related loss of nitric oxide synthase in skeletal muscle causes reductions in calpain S‐nitrosylation that increase myofibril degradation and sarcopenia. Aging Cell. 2012; 11: 1036– 1045. 22950758 PMC3734855 sourceNot checked yet

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Clinical data showed that skeletal muscle fat infiltration occurred in both lean and obese individuals, although the infiltrated muscle volume was positively associated with body mass index (BMI).

“Clinical data showed that skeletal muscle fat infiltration occurred in both lean and obese individuals, although the infiltrated muscle volume was positively associated with body mass index (BMI).[ 11 ]”

• cites [11] Vivodtzev I, Moncharmont L, Tamisier R, Borel JC, Arbib F, Wuyam B, et al. Quadriceps muscle fat infiltration is associated with cardiometabolic risk in COPD. Clin Physiol Funct Imaging. 2018; 38: 788– 797. 29105276 sourceNot checked yet

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May combine two claims.

During ageing, an attenuated Notch signalling response results in impaired proliferation of satellite cells and a failure in muscle regeneration.

“During ageing, an attenuated Notch signalling response results in impaired proliferation of satellite cells and a failure in muscle regeneration.[ 44 ]”

• cites [44] Conboy IM, Conboy MJ, Smythe GM, Rando TA. Notch‐mediated restoration of regenerative potential to aged muscle. Science. 2003; 302: 1575– 1577. 14645852 sourceNot checked yet

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As a result of mitochondrial dysfunction with ageing, the lipid oxidation-induced ROS and local inflammation lead to the activation of stress signalling pathways, such as c-Jun N-terminal kinase (JNK), IκB kinase (IKK), protein kinase C (PKC) and p38-mitogen-activated protein kinase (p38-MAPK), all of which also suppress insulin-PI3K-mTOR signalling.

“But as a result of mitochondrial dysfunction with ageing, the lipid oxidation‐induced ROS and local inflammation lead to the activation of stress signalling pathways, such as c‐Jun N‐terminal kinase (JNK), IκB kinase (IKK), protein kinase C (PKC) and p38‐mitogen‐activated protein kinase (p38‐MAPK), all of which also suppress insulin‐PI3K‐mTOR signalling.[ 54 ]”

• cites [54] Aon MA, Bhatt N, Cortassa SC. Mitochondrial and cellular mechanisms for managing lipid excess. Front Physiol. 2014; 5: 282. 25132820 PMC4116787 sourceNot checked yet

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TGF-β is a Notch inhibitor upregulated during ageing and may explain the spontaneous entry of satellite cells into the cell cycle during ageing.

“Furthermore, TGF‐β is a Notch inhibitor upregulated during ageing and may explain the spontaneous entry of satellite cells into the cell cycle during ageing.[ 45 ]”

• cites [45] Xiao ZC, Zhang J, Peng XG, Dong YJ, Jia LX, Li HH Jr, et al. The Notch γ‐secretase inhibitor ameliorates kidney fibrosis via inhibition of TGF‐β/Smad2/3 signaling pathway activation. Int J Biochem Cell Biol. 2014; 55: 65– 71. 25150830 sourceNot checked yet

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Fat redistribution is a hallmark of modern ageing that has been validated amongst nonagenarians as well.

“Fat redistribution is a hallmark of modern ageing that has been validated amongst nonagenarians as well.[ 10 ]”

• cites [10] Idoate F, Cadore EL, Casas‐Herrero A, Zambom‐Ferraresi F, Marcellan T, Gordoa AR, et al. Adipose tissue compartments, muscle mass, muscle fat infiltration, and coronary calcium in institutionalized frail nonagenarians. Eur Radiol. 2015; 25: 2163– 2175. 25510447 sourceNot checked yet

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May combine two claims.

Inflammaging, defined as the increase in senescence-associated secretory phenotype (SASP) inflammatory cytokines with ageing, can spread this metabolic dysfunction systemically as this low-grade chronic inflammatory state spreads inflammation-induced IR, lipid dysfunction, and senescence across the adipose depots, muscles and other tissues.

“Inflammaging, defined as the increase in senescence‐associated secretory phenotype (SASP) inflammatory cytokines with ageing, can spread this metabolic dysfunction systemically as this low‐grade chronic inflammatory state spreads inflammation‐induced IR, lipid dysfunction, and senescence across the adipose depots, muscles and other tissues.[ 57 ]”

• cites [57] Lackey DE, Olefsky JM, et al. Regulation of metabolism by the innate immune system. Nat Rev Endocrinol. 2016; 12(1): 15– 28. 26553134 sourceNot checked yet

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Skeletal muscle fat infiltration appears to be independent of muscle mass, suggesting it precedes muscle atrophy to cause sarcopenia.

“Skeletal muscle fat infiltration appears to be independent of muscle mass, however, suggesting it precedes muscle atrophy to cause sarcopenia.[ 37 ]”

• cites [37] Nachit M, Rudder MD, Thissen JP, Schakman O, Bouzin C, Horsmans Y, et al. Myosteatosis rather than sarcopenia associates with non‐alcoholic steatohepatitis in non‐alcoholic fatty liver disease preclinical models. J Cachexia Sarcopenia Muscle. 2021; 12: 144– 158. 33244884 PMC7890270 sourceNot checked yet

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Chronic inflammation in extant adipose depots and other tissues also contribute to the pathophysiology of adipose tissue dysfunction, including the gradual impairment of adipogenesis that contributes to IR and metabolic disease.

“Chronic inflammation in extant adipose depots and other tissues also contribute to the pathophysiology of adipose tissue dysfunction, including the gradual impairment of adipogenesis that contributes to IR and metabolic disease.[ 23 ]”

• cites [23] Ghaben AL, Scherer PE. Adipogenesis and metabolic health. Nat Rev Mol Cell Biol. 2019; 20: 242– 258. 30610207 sourceNot checked yet

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Skeletal muscle ectopic fat infiltration, or myosteatosis, is an abnormal phenomenon that increases with ageing and is recognized to negatively correlate with muscle mass, strength, mobility and normal metabolism.

“Skeletal muscle ectopic fat infiltration, or myosteatosis, is an abnormal phenomenon that increases with ageing and is recognized to negatively correlate with muscle mass, strength, mobility and normal metabolism.[ 37 ]”

• cites [37] Nachit M, Rudder MD, Thissen JP, Schakman O, Bouzin C, Horsmans Y, et al. Myosteatosis rather than sarcopenia associates with non‐alcoholic steatohepatitis in non‐alcoholic fatty liver disease preclinical models. J Cachexia Sarcopenia Muscle. 2021; 12: 144– 158. 33244884 PMC7890270 sourceNot checked yet

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Local muscle IR leads to reduced lipid uptake and increases local free fatty acid (FFA) concentrations, thereby worsening the local hyperlipidaemia and local IMAT inflammation, and boosting the secretion of inflammatory factors by both adipose and muscle tissues.

“One important reason is that the local muscle IR leads to reduced lipid uptake and increases local free fatty acid (FFA) concentrations, thereby worsening the local hyperlipidaemia and local IMAT inflammation, as explained in the earlier section, and boosting the secretion of inflammatory factors by both adipose and muscle tissues.[ 56 ]”

• cites [56] Sachs S, Zarini S, Kahn DE, Harrison KA, Perreault L, Phang T, et al. Intermuscular adipose tissue directly modulates skeletal muscle insulin sensitivity in humans. Am J Physiol Endocrinol Metab. 2019; 316: E866– E879. 30620635 PMC6580171 sourceNot checked yet

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Many 'normal' subjects in current studies could actually be SO subjects that were not suspected nor tested for (pre-)sarcopenia, and we might be grossly underestimating both the prevalence and the impact of SO.

“This means many ‘normal’ subjects in current studies could actually be SO subjects that were not suspected nor tested for (pre‐)sarcopenia, and we might be grossly underestimating both the prevalence and the impact of SO.”

May combine two claims.

Inflammation-induced lipolysis, hyperlipidaemia, and the progressive redistribution of lipids to newly formed visceral fat depots and nearby muscles lead to ectopic fat infiltration in many organs.

“Inflammation‐induced lipolysis, hyperlipidaemia, and the progressive redistribution of lipids to newly formed visceral fat depots and nearby muscles lead to ectopic fat infiltration in many organs.”

May combine two claims.

It was local hyperlipidaemia, lipotoxicity, and IR that triggered the local inflammaging, which worsened the lipid metabolism dysfunction in a spreading vicious cycle.

“Notably, it was local hyperlipidaemia, lipotoxicity, and IR that triggered the local inflammaging, which worsened the lipid metabolism dysfunction in a spreading vicious cycle.”

May combine two claims.

Excess lipids are thought to 'spill over' to other tissues, especially the skeletal muscles, which accumulate the lipids as intermuscular adipose tissue (IMAT), intramuscular adipose tissue and intramyocellular lipid droplets (IMCLs) containing triacylglycerol or fatty acid derivatives such as diacylglycerols (DAG), long chain acyl CoAs, and ceramides.

“Excess lipids are thought to ‘spill over’ to other tissues, especially the skeletal muscles,[ 35 ] which accumulate the lipids as intermuscular adipose tissue (IMAT), intramuscular adipose tissue and intramyocellular lipid droplets (IMCLs) containing triacylglycerol or fatty acid derivatives such as diacylglycerols (DAG), long chain acyl CoAs, and ceramides.[ 36 ]”

• cites [35] Pienkowska J, Brzeska B, Kaszubowski M, Kozak O, Jankowska A, Szurowska E. MRI assessment of ectopic fat accumulation in pancreas, liver and skeletal muscle in patients with obesity, overweight and normal BMI in correlation with the presence of central obesity and metabolic syndrome. Diabetes Metab Syndr Obes. 2019; 12: 623– 636. 31118724 PMC6506015 sourceNot checked yet

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• cites [36] Ritter O, Jelenik T, Roden M. Lipid‐mediated muscle insulin resistance: different fat, different pathways? J Mol Med (Berl). 2015; 93: 831– 843. 26108617 sourceNot checked yet

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In a chronic inflammation microenvironment, preadipocytes can transdifferentiate into macrophage-like cells, with increased expression of pro-inflammatory cytokines and decreased adipogenic capacity in response to inflammatory stimuli.

“In a chronic inflammation microenvironment, preadipocytes can transdifferentiate into macrophage‐like cells, with increased expression of pro‐inflammatory cytokines and decreased adipogenic capacity in response to inflammatory stimuli.[ 34 ]”

• cites [34] Isakson P, Hammarstedt A, Gustafson B, Smith U. Impaired preadipocyte differentiation in human abdominal obesity: role of Wnt, tumor necrosis factor‐alpha, and inflammation. Diabetes. 2009; 58: 1550– 1557. 19351711 PMC2699851 sourceNot checked yet

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In the longitudinal Korean Sarcopenic Obesity Study, the extent of visceral obesity at the start of the study was shown to correlate with the extent of appendicular muscle loss over ~2 years of follow-up, indicating that fat redistribution may play a causal role in this association.

“Nevertheless, in the longitudinal Korean Sarcopenic Obesity Study, the extent of visceral obesity at the start of the study was shown to correlate with the extent of appendicular muscle loss over ~2 years of follow‐up, indicating that fat redistribution may play a causal role in this association.[ 61 ]”

• cites [61] Kim TN, Park MS, Ryu JY, Choi HY, Hong HC, Yoo YJ, et al. Impact of visceral fat on skeletal muscle mass and vice versa in a prospective cohort study: the Korean Sarcopenic Obesity Study (KSOS). PLoS One. 2014; 9: e115407. 25517117 PMC4269440 sourceNot checked yet

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The impaired insulin-PI3K-mTOR signalling further inhibits muscle mitochondrial function, leading to further lipid accumulation and lipid oxidation-induced ROS, thus creating a vicious cycle of myosteatosis, lipotoxicity and muscle IR with ageing.

“In addition, the impaired insulin‐PI3K‐mTOR signalling further inhibits muscle mitochondrial function, leading to further lipid accumulation and lipid oxidation‐induced ROS, thus creating a vicious cycle of myosteatosis, lipotoxicity and muscle IR with ageing.[ 55 ]”

• cites [55] Kim KH, Choi S, Zhou Y, Kim EY, Lee JY, Saha PK, et al. Hepatic FXR/SHP axis modulates systemic glucose and fatty acid homeostasis in aged mice. Hepatology. 2017; 66: 498– 509. 28378930 PMC8156739 sourceNot checked yet

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The pro-inflammatory factors further induce infiltration of macrophages and other immune cells into adipose, muscle and other tissues, which further secrete a large amount of pro-inflammatory cytokines and chemokines, thus broadening the local chronic inflammation into a systemic inflammaging condition in adipose depots, muscles and other tissues.

“The pro‐inflammatory factors further induce infiltration of macrophages and other immune cells into adipose, muscle and other tissues, which further secrete a large amount of pro‐inflammatory cytokines and chemokines, thus broadening the local chronic inflammation into a systemic inflammaging condition in adipose depots, muscles and other tissues.[ 57 ]”

• cites [57] Lackey DE, Olefsky JM, et al. Regulation of metabolism by the innate immune system. Nat Rev Endocrinol. 2016; 12(1): 15– 28. 26553134 sourceNot checked yet

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Full-blown sarcopenia often leads to loss of respiratory function, and increased risk of death.

“Full‐blown sarcopenia, on the other hand, often leads to loss of respiratory function, and increased risk of death.[ 4 ]”

• cites [4] Kob R, Fellner C, Bertsch T, Wittmann A, Mishura D, Sieber CC, et al. Gender‐specific differences in the development of sarcopenia in the rodent model of the ageing high‐fat rat. J Cachexia Sarcopenia Muscle. 2015; 6: 181– 191. 26136194 PMC4458084 sourceNot checked yet

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Our metabaging theory that SO progresses to sarcopenia, and extensive evidence presented, further suggests that higher mortality in 'normal BMI' elderly groups might also be partly because underlying chronic disease has actually progressed to point of being associated with full-blown sarcopenia, instead of SO, in some patients.

“Our metabaging theory that SO progresses to sarcopenia, and the extensive evidence presented in sections, further suggests that the higher mortality in the ‘normal BMI’ elderly groups might also be partly because the underlying chronic disease has actually progressed to the point of being associated with full‐blown sarcopenia, instead of SO, in some patients.”

• AssumptionRests on an assumption: Sarcopenic obesity patients may appear as 'normal' subjects due to the mutual masking effect of sarcopenia and obesity.

May combine two claims.

Current BIA devices cannot accurately quantify muscle mass, for it indirectly reflects whole body composition, which is influenced by fluid and food intake, internal body fat, and disease-related conditions.

“However, current BIA devices cannot accurately quantify muscle mass, for it indirectly reflects whole body composition, which is influenced by fluid and food intake, internal body fat, and disease‐related conditions.[ 115 ]”

• cites [115] Wang M, Tan Y, Shi Y, Wang X, Liao Z, Wei P, et al. Diabetes and Sarcopenic Obesity: Pathogenesis, Diagnosis, and Treatments. Front Endocrinol (Lausanne). 2020; 11: 568. 32982969 PMC7477770 sourceNot checked yet

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SO is frequently associated with increased risk of chronic disease incidence, while full-blown sarcopenia is frequently associated with increased chronic disease severity and risk of death.

“Thus, it seems that SO is frequently associated with increased risk of chronic disease incidence, while full‐blown sarcopenia is frequently associated with increased chronic disease severity and risk of death.”

May combine two claims.

Under pathological conditions, TWEAK becomes overexpressed and activates NF-κB pathway via FGF-inducible 14 receptors, leading to increased MuRF1 expression and activation of UPS pathway.

“Under pathological conditions, TWEAK also becomes overexpressed and activates the NF‐κB pathway via the FGF‐inducible 14 receptors, leading to increased expression of MuRF1 and activation of the ubiquitin‐proteasome (UPS) pathway as well.[ 69 ]”

• cites [69] Li CW, Yu K, Ng SC, Li GX, Jiang LJ, Yu SL, et al. Circulating factors associated with sarcopenia during ageing and after intensive lifestyle intervention. J Cachexia Sarcopenia Muscle.. 2019; 10: 586– 600. 30969486 PMC6596393 sourceNot checked yet

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May combine two claims.

These pathogenic B cells activate IFNγ-producing CD4+ and CD8+ T cells and/or IL-17-secreting Th1 cells within the visceral adipose tissues, presumably through LTB4/leukotriene-B4 receptor 1 (LTB4R1) signalling.

“These pathogenic B cells activate IFNγ‐producing CD4+ and CD8 + T cells and/or IL‐17‐secreting Th1 cells within the visceral adipose tissues, presumably through LTB4/leukotriene‐B4 receptor 1 (LTB4R1) signalling.”

• cites [68] DeFuria J, Belkina AC, Jagannathan‐Bogdan M, Snyder‐Cappione J, Carr JD, Nersesova YR, et al. B cells promote inflammation in obesity and type 2 diabetes through regulation of T‐cell function and an inflammatory cytokine profile. Proc Natl Acad Sci USA. 2013; 110: 5133– 5138. 23479618 PMC3612635 sourceNot checked yet

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Classified as probably not a substantial claim.

In context of sarcopenia, obesity might be 'protective' against chronic disease severity and death, similar to 'obesity paradox'.

“On the other hand, in the context of sarcopenia, this might also suggest that obesity might be ‘protective’ against chronic disease severity and death, a phenomenon similar to the ‘obesity paradox’.”

May combine two claims.

SO was associated with a higher risk of hypertension, dyslipidaemia and IR, and up to an 8-fold increased risk for metabolic syndrome compared with non-sarcopenic and non-obese subjects.

“SO was associated with a higher risk of hypertension, dyslipidaemia and IR, and up to an 8‐fold increased risk for the metabolic syndrome compared with non‐sarcopenic and non‐obese subjects.[ 90 ]”

• cites [90] Kim TN, Park MS, Lim KI, Choi HY, Yang SJ, Yoo HJ, et al. Relationships between sarcopenic obesity and insulin resistance, inflammation, and vitamin D status: the Korean Sarcopenic Obesity Study. Clin Endocrinol (Oxf). 2013; 78: 525– 532. 22563924 sourceNot checked yet

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May combine two claims.

This is accompanied by significant functional disturbances, such as reduced lipid β-oxidation of fatty acids and lipolysis, resulting in systemic IR.

“This is accompanied by significant functional disturbances, such as reduced lipid β‐oxidation of fatty acids and lipolysis,[ 64 ] resulting in systemic IR.”

• cites [64] Shulman GI. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med. 2014; 371: 2237– 2238. 25470706 sourceNot checked yet

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May combine two claims.

Atrogenes trigger UPS and lysosome-autophagy system that significantly contribute to disturbed mitochondrial fission and muscle remodelling, causing severe muscle atrophy.

“In turn, the atrogenes trigger the UPS and the lysosome‐autophagy system that significantly contribute to disturbed mitochondrial fission and muscle remodelling, causing severe muscle atrophy.”

May combine two claims.

Ectopic lipids induce Nod-like receptors protein 3 (NLRP3) inflammasome formation to trigger caspase-1, which subsequently activate IL-1β and IL-18, thus activating the pro-inflammatory M1 macrophages resident in the skeletal muscle.

“For example, ectopic lipids induce Nod‐like receptors protein 3 (NLRP3) inflammasome formation to trigger caspase‐1, which subsequently activate IL‐1β and IL‐18, thus activating the pro‐inflammatory M1 macrophages resident in the skeletal muscle.[ 66 ]”

• cites [66] Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, et al. The NALP3/NLRP3 Inflammasome Instigates Obesity‐Induced Autoinflammation and Insulin Resistance. Nat Med. 2011; 17: 179– 188. 21217695 PMC3076025 sourceNot checked yet

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Lipolysis in VAT enables direct delivery of FFAs to liver, which may lead to elevated hepatic TG production, increased VLDL secretion, and higher plasma TGs, exacerbating hyperlipidaemia.

“Lipolysis in VAT enables direct delivery of FFAs to the liver, which may lead to elevated hepatic triglyceride (TG) production, increased very low‐density lipoprotein secretion, and higher plasma TGs which exacerbates an already dysregulated hyperlipidaemic state.[ 79 ]”

• cites [79] Hellmer J, Marcus C, Sonnenfeld T, Arner P. Mechanisms for differences in lipolysis between human subcutaneous and omental fat cells. J Clin Endocrinol Metab. 1992; 75: 15– 20. 1320047 sourceNot checked yet

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May combine two claims.

These macrophages release TNFα, IL-1β, IL-6, monocyte-chemoattractant protein-1 (MCP-1), and TGFβ, which can also stimulate trans-differentiation of fibroblasts into myofibroblasts to cause fibrosis and further tissue damage, worsening the systemic inflammaging.

“These macrophages release TNFα, IL‐1β, IL‐6, monocyte‐chemoattractant protein‐1 (MCP‐1), and TGFβ, which can also stimulate trans‐differentiation of fibroblasts into myofibroblasts to cause fibrosis and further tissue damage, worsening the systemic inflammaging.”

• cites [66] Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, et al. The NALP3/NLRP3 Inflammasome Instigates Obesity‐Induced Autoinflammation and Insulin Resistance. Nat Med. 2011; 17: 179– 188. 21217695 PMC3076025 sourceNot checked yet

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May combine two claims.

Fat mass is merely another effect of cancer progression, the ultimate cause of mortality in these cases.

“Thus, fat mass is merely another effect of cancer progression, the ultimate cause of mortality in these cases.”

May combine two claims.

Pro-inflammatory cytokines TNFα and IL-1β blunt local IGF-1 expression, leading to impairment of glucose disposal into muscle and resistance of mTORC1 activation from IRS1 phosphorylation and downstream cascade.

“Additionally, the local expression of IGF‐1 is blunted by pro‐inflammatory cytokines TNFα and IL‐1β, leading to impairment of glucose disposal into the muscle and the resistance of mTORC1 activation from insulin receptor substrate 1 (IRS1) phosphorylation and its downstream cascade, an example of the synergy between IR and anabolic resistance.[ 70 ]”

• cites [70] Kawakami M, Murase T, Ogawa H, Ishibashi S, Mori N, Takaku F, et al. Human recombinant TNF suppresses lipoprotein lipase activity and stimulates lipolysis in 3T3‐L1 cells. J Biochem. 1987; 101: 331– 338. 3495531 sourceNot checked yet

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May combine two claims.

Enhanced release of fatty acids and dysregulated production of adipokines can activate and recruit macrophages via binding chemokine (C-C motif) receptor 2 (CCR2), CD36 and/or toll-like receptor 4 (TLR4), as well as other immune cells via activation of adhesion molecules and triggering chemotaxis, worsening the pro-inflammatory vicious cycle.

“Enhanced release of fatty acids and dysregulated production of adipokines can activate and recruit macrophages via binding chemokine (C‐C motif) receptor 2 (CCR2), CD36 and/or toll‐like receptor 4 (TLR4),[ 65 ] as well as other immune cells via activation of adhesion molecules and triggering chemotaxis, worsening the pro‐inflammatory vicious cycle.”

• cites [65] Li L, Renier G. Adipocyte‐derived lipoprotein lipase induces macrophage activation and monocyte adhesion: role of fatty acids. Obesity (Silver Spring). 2007; 15: 102920, 2595– 2604. 18070750 sourceNot checked yet

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