Molecular Mechanisms of Inflammation in Sarcopenia: Diagnosis and Therapeutic Update

Jiménez-Gutiérrez, Guadalupe Elizabeth; Martínez-Gómez, Laura E.; Martínez-Armenta, Carlos; Pineda, Carlos; Martínez‐Nava, Gabriela Angélica; López‐Reyes, Alberto

doi:10.3390/cells11152359

Cited by 53 publications

(38 citation statements)

References 155 publications

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“…Diabetic sarcopenia is an inevitable complication of T2DM, characterized by three major features, that is, decreased muscle mass, weakened muscle strength and reduced physical performance 1 . In our study, the diabetic mice demonstrated the above features, suggesting obvious sarcopenia.…”

Section: Discussionsupporting

confidence: 54%

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Stimulator of interferon genes promotes diabetic sarcopenia by targeting peroxisome proliferator activated receptors γ degradation and inhibiting fatty acid oxidation

Yan,

Liang,

Zhan

et al. 2023

J cachexia sarcopenia muscle

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BackgroundDeclined skeletal muscle mass and function are inevitable consequences of long‐term diabetes and bring about many adverse events. Muscle fibre atrophy and interstitial fibrosis are major pathological manifestations of diabetic sarcopenia. Stimulator of interferon genes (STING) participates in various metabolic diseases. We aimed to explore whether and how STING regulates the above pathological manifestations of diabetic sarcopenia.MethodsWild‐type and STINGgt/gt C57BL/6J mice and C2C12 myotubes were used to study the role of STING in the regulation of diabetic sarcopenia and the underlying mechanisms.ResultsSTING was abnormally activated in diabetic muscles and in PA‐treated myotubes (P < 0.01 for all parameters). The diabetic mice demonstrated decreased forelimb grip strength, lean mass, muscle weight and hanging impulse, which were improved by STING deficiency due to alleviated muscle fibre atrophy and interstitial fibrosis (P < 0.05 for all parameters). STING deficiency alleviated muscle fibre atrophy through the following mechanisms. Firstly, STING deficiency or inhibition increased the contents of pDRP1Ser616, PINK1, Parkin and LC3‐II, decreased p62 content, and increased the amount of mito‐Keima fluorescent dots at 578 nm in diabetic state (P < 0.05 for all parameters), suggesting improved mitofission and mitophagy. Secondly, STING deficiency or inhibition increased the expression of pAKTSer473 and GLUT4 post‐insulin change in diabetic state (P < 0.05 for all), indicating alleviated insulin resistance (IR). Mechanically, STING deficiency or inhibition increased peroxisome proliferator activated receptors γ (PPARγ) protein content by reducing the degradation of ubiquitinated PPARγ through the proteasome pathway and thus increased the expression of fatty acid oxidation (FAO)‐related proteins in diabetic state (P < 0.05 for all parameters). Decreased expression of FAO‐related proteins caused by PPARγ inhibition abolished the improvements in mitofission, mitophagy and IR achieved by STING inhibition in PA‐treated myotubes and thus promoted muscle fibre atrophy (P < 0.05 for all parameters). STING deficiency alleviated interstitial fibrosis by decreasing TGFβ1 expression in diabetic state and TGFβ1 promoted the fibrogenic differentiation of fibro‐adipogenic progenitors (P < 0.05 for all parameters). PPARγ inhibition abolished the effect of STING inhibition on reducing TGFβ1 content in PA‐treated myotubes (P < 0.01).ConclusionsSTING deficiency exerted protective effects in diabetic sarcopenia by inhibiting the degradation of ubiquitinated PPARγ through the proteasome pathway and enhancing PPARγ‐mediated FAO, which alleviated muscle fibre atrophy by promoting mitophagy and ameliorating IR, and alleviated interstitial fibrosis by reducing TGFβ1 production and suppressing the fibrogenic differentiation of fibro‐adipogenic progenitors.

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Section: Discussionsupporting

confidence: 54%

“…Sarcopenia is a degenerative syndrome characterized by declined muscle mass, muscle strength and physical performance and leads to frailty, falls, physical disability and even mortality 1,2 . Diabetes mellitus (DM) has been reported as a common risk factor for sarcopenia.…”

Section: Introductionmentioning

confidence: 99%

Stimulator of interferon genes promotes diabetic sarcopenia by targeting peroxisome proliferator activated receptors γ degradation and inhibiting fatty acid oxidation

Yan,

Liang,

Zhan

et al. 2023

J cachexia sarcopenia muscle

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“…Pyroptosis can cause inflammation that is activated by extracellular or intracellular stimuli [ 52 ] and is associated with various diseases, such as cardiovascular disease [ 53 ], Alzheimer’s disease [ 54 ], atherosclerosis [ 55 ], and muscle atrophy [ 56 ]. A recent study showed that pyroptosis occurs during dexamethasone-induced muscle atrophy [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

The Inhibition of Autophagy and Pyroptosis by an Ethanol Extract of Nelumbo nucifera Leaf Contributes to the Amelioration of Dexamethasone-Induced Muscle Atrophy

et al. 2023

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Muscle atrophy is characterized by a decline in muscle mass and function. Excessive glucocorticoids in the body due to aging or drug treatment can promote muscle wasting. In this study, we investigated the preventive effect of Nelumbo nucifera leaf (NNL) ethanolic extract on muscle atrophy induced by dexamethasone (DEX), a synthetic glucocorticoid, in mice and its underlying mechanisms. The administration of NNL extract increased weight, cross-sectional area, and grip strength of quadriceps (QD) and gastrocnemius (GA) muscles in DEX-induced muscle atrophy in mice. The NNL extract administration decreased the expression of muscle atrophic factors, such as muscle RING-finger protein-1 and atrogin-1, and autophagy factors, such as Beclin-1, microtubule-associated protein 1A/1B-light chain 3 (LC3-I/II), and sequestosome 1 (p62/SQSTM1) in DEX-injected mice. DEX injection increased the protein expression levels of NOD-like receptor pyrin domain-containing protein 3 (NLRP3), cleaved-caspase-1, interleukin-1beta (IL-1β), and cleaved-gasdermin D (GSDMD), which were significantly reduced by NNL extract administration (500 mg/kg/day). In vitro studies using C2C12 myotubes also revealed that NNL extract treatment inhibited the DEX-induced increase in autophagy factors, pyroptosis-related factors, and NF-κB. Overall, the NNL extract prevented DEX-induced muscle atrophy by downregulating the ubiquitin–proteasome system, autophagy pathway, and GSDMD-mediated pyroptosis pathway, which are involved in muscle degradation.

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“…Immunomodulation is also a relevant therapeutic approach for other pathological skeletal muscle conditions, such as sarcopenia, or the loss of muscle mass that occurs with age. Sarcopenia is associated with changes in the skeletal muscle microenvironment, such as an imbalanced inflammatory infiltrate and high levels of pro-inflammatory cytokines [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Nano-Immunomodulation: A New Strategy for Skeletal Muscle Diseases and Aging?

Millozzi

Papait

Bouché

et al. 2023

IJMS

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The skeletal muscle has a very remarkable ability to regenerate upon injury under physiological conditions; however, this regenerative capacity is strongly diminished in physio-pathological conditions, such as those present in diseased or aged muscles. Many muscular dystrophies (MDs) are characterized by aberrant inflammation due to the deregulation of both the lymphoid and myeloid cell populations and the production of pro-inflammatory cytokines. Pathological inflammation is also observed in old muscles due to a systemic change in the immune system, known as “inflammaging”. Immunomodulation represents, therefore, a promising therapeutic opportunity for different skeletal muscle conditions. However, the use of immunomodulatory drugs in the clinics presents several caveats, including their low stability in vivo, the need for high doses to obtain therapeutically relevant effects, and the presence of strong side effects. Within this context, the emerging field of nanomedicine provides the powerful tools needed to control the immune response. Nano-scale materials are currently being explored as biocarriers to release immunomodulatory agents in the damaged tissues, allowing therapeutic doses with limited off-target effects. In addition, the intrinsic immunomodulatory properties of some nanomaterials offer further opportunities for intervention that still need to be systematically explored. Here we exhaustively review the state-of-the-art regarding the use of nano-sized materials to modulate the aberrant immune response that characterizes some physio-pathological muscle conditions, such as MDs or sarcopenia (the age-dependent loss of muscle mass). Based on our learnings from cancer and immune tolerance induction, we also discuss further opportunities, challenges, and limitations of the emerging field of nano-immunomodulation.

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Molecular Mechanisms of Inflammation in Sarcopenia: Diagnosis and Therapeutic Update

Cited by 53 publications

References 155 publications

Stimulator of interferon genes promotes diabetic sarcopenia by targeting peroxisome proliferator activated receptors γ degradation and inhibiting fatty acid oxidation

Stimulator of interferon genes promotes diabetic sarcopenia by targeting peroxisome proliferator activated receptors γ degradation and inhibiting fatty acid oxidation

The Inhibition of Autophagy and Pyroptosis by an Ethanol Extract of Nelumbo nucifera Leaf Contributes to the Amelioration of Dexamethasone-Induced Muscle Atrophy

Nano-Immunomodulation: A New Strategy for Skeletal Muscle Diseases and Aging?

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