Chronic heart failure （CHF） is a highly prevalent condition among the elderly and is associated with considerable morbidity, institution-alization and mortality. In its advanced stages, CHF is often accompanied by t...Chronic heart failure （CHF） is a highly prevalent condition among the elderly and is associated with considerable morbidity, institution-alization and mortality. In its advanced stages, CHF is often accompanied by the loss of muscle mass and strength. Sarcopenia is a geriatric syndrome that has been actively studied in recent years due to its association with a wide range of adverse health outcomes. The goal of this review is to discuss the relationship between CHF and sarcopenia, with a focus on shared pathophysiological pathways and treatments. Mal- nutrition, systemic inflammation, endocrine imbalances, and oxidative stress appear to connect sarcopenia and CHF. At the muscular level, alterations of the ubiquitin proteasome system, myostatin signaling, and apoptosis have been described in both sarcopenia and CHF and could play a role in the loss of muscle mass and function. Possible therapeutic strategies to impede the progression of muscle wasting in CHF patients include protein and vitamin D supplementation, structured physical exercise, and the administration of angiotensin-converting enzyme inhibitors and β-blockers. Hormonal supplementation with growth hormone, testosterone, and ghrelin is also discussed as a potential treatment.展开更多
Colorectal cancer(CRC)is the third most commonly diagnosed cancer globally and the second cancer in terms of mortality.The prevalence of sarcopenia in patients with CRC ranges between 12%-60%.Sarcopenia comes from the...Colorectal cancer(CRC)is the third most commonly diagnosed cancer globally and the second cancer in terms of mortality.The prevalence of sarcopenia in patients with CRC ranges between 12%-60%.Sarcopenia comes from the Greek“sarx”for flesh,and“penia”for loss.Sarcopenia is considered a phenomenon of the aging process and precedes the onset of frailty(primary sarcopenia),but sarcopenia may also result from pathogenic mechanisms and that disorder is termed secondary sarcopenia.Sarcopenia diagnosis is confirmed by the presence of low muscle quantity or quality.Three parameters need to be measured:muscle strength,muscle quantity and physical performance.The standard method to evaluate muscle mass is by analyzing the tomographic total cross-sectional area of all muscle groups at the level of lumbar 3rd vertebra.Sarcopenia may negatively impact on the postoperative outcomes of patients with colorectal cancer undergoing surgical resection.It has been described an association between sarcopenia and numerous poor short-term CRC outcomes like increased perioperative mortality,postoperative sepsis,prolonged length of stay,increased cost of care and physical disability.Sarcopenia may also negatively impact on overall survival,disease-free survival,recurrence-free survival,and cancerspecific survival in patients with non-metastatic and metastatic colorectal cancer.Furthermore,patients with sarcopenia seem prone to toxic effects during chemotherapy,requiring dose deescalations or treatment delays,which seems to reduce treatment efficacy.A multimodal approach including nutritional support(dietary intake,high energy,high protein,and omega-3 fatty acids),exercise programs and anabolic-orexigenic agents(ghrelin,anamorelin),could contribute to muscle mass preservation.Addition of sarcopenia screening to the established clinical-pathological scores for patients undergoing oncological treatment(chemotherapy,radiotherapy or surgery)seems to be the next step for the best of care of CRC patients.展开更多
Muscle flaps must have a strong vascular network to support a large tissue volume and ensure successful engraftment.We developed porcine stomach musculofascial flap matrix(PDSF)comprising extracellular matrix(ECM)and ...Muscle flaps must have a strong vascular network to support a large tissue volume and ensure successful engraftment.We developed porcine stomach musculofascial flap matrix(PDSF)comprising extracellular matrix(ECM)and intact vasculature.PDSF had a dominant vascular pedicle,microcirculatory vessels,a nerve network,well-retained 3-dimensional(3D)nanofibrous ECM structures,and no allo-or xenoantigenicity.In-depth proteomic analysis demonstrated that PDSF was composed of core matrisome proteins(e.g.,collagens,glycoproteins,proteoglycans,and ECM regulators)that,as shown by Gene Ontology term enrichment analysis,are functionally related to musculofascial biological processes.Moreover,PDSFhuman adipose-derived stem cell(hASC)synergy not only induced monocytes towards IL-10producing M2 macrophage polarization through the enhancement of hASCs’paracrine effect but also promoted the proliferation and interconnection of both human skeletal muscle myoblasts(HSMMs)and human umbilical vein endothelial cells(HUVECs)in static triculture conditions.Furthermore,PDSF was successfully prevascularized through a dynamic perfusion coculture of hASCs and HUVECs,which integrated with PDSF and induced the maturation of vascular networks in vitro.In a xenotransplantation model,PDSF demonstrated myoconductive and immunomodulatory properties associated with the predominance of M2 macrophages and regulatory T cells.In a volumetric muscle loss(VML)model,prevascularized PDSF augmented neovascularization and constructive remodeling,which was characterized by the predominant infiltration of M2 macrophages and significant musculofascial tissue formation.These results indicate that hASCs’integration with PDSF enhances the cells’dual function in immunomodulation and angiogenesis.Owing in part to this PDSF-hASC synergy,our platform shows promise for vascularized muscle flap engineering for VML reconstruction.展开更多
Nicotinamide adenine dinucleotide(NADH)is a cofactor that serves to shuttle electrons during metabolic processes such as glycolysis,the tricarboxylic acid cycle,and oxidative phosphorylation(OXPHOS).NADH is autofluore...Nicotinamide adenine dinucleotide(NADH)is a cofactor that serves to shuttle electrons during metabolic processes such as glycolysis,the tricarboxylic acid cycle,and oxidative phosphorylation(OXPHOS).NADH is autofluorescent,and itsfluorescence lifetime can be used to infer metabolic dynamics in living cells.Fiber-coupled time-correlated single photon counting(TCSPC)equipped with an implantable needle probe can be used to measure NADH lifetime in vivo,enabling investigation of changing metabolic demand during muscle contraction or tissue regeneration.This study illustrates a proof of concept for point-based,minimally-invasive NADHfluorescence lifetime measurement in vivo.Volumetric muscle loss(VML)injuries were created in the left tibialis anterior(TA)muscle of male Sprague Dawley rats.NADH lifetime measurements were collected before,during,and after a 30 s tetanic contraction in the injured and uninjured TA muscles,which was subsequently-t to a biexponential decay model to yield a metric of NADH utilization(cytoplasmic vs protein-bound NADH,the A11/A22 ratio).On average,this ratio was higher during and after contraction in uninjured muscle compared to muscle at rest,suggesting higher levels of free NADH in contracting and recovering muscle,indicating increased rates of glycolysis.In injured muscle,this ratio was higher than uninjured muscle overall but decreased over time,which is consistent with current knowledge of inflammatory response to injury,suggesting tissue regeneration has occurred.These data suggest that-ber-coupled TCSPC has the potential to measure changes in NADH binding in vivo in a minimally invasive manner that requires further investigation.展开更多
Current therapeutic approaches for volumetric muscle loss(VML)face challenges due to limited graft availability and insufficient bioactivities.To overcome these limitations,tissue-engineered scaffolds have emerged as ...Current therapeutic approaches for volumetric muscle loss(VML)face challenges due to limited graft availability and insufficient bioactivities.To overcome these limitations,tissue-engineered scaffolds have emerged as a promising alternative.In this study,we developed aligned ternary nanofibrous matrices comprised of poly(lactide-co-ε-caprolactone)integrated with collagen and Ti_(3)C_(2)T_(x)MXene nanoparticles(NPs)(PCM matrices),and explored their myogenic potential for skeletal muscle tissue regeneration.The PCM matrices demonstrated favorable physicochemical properties,including structural uniformity,alignment,microporosity,and hydrophilicity.In vitro assays revealed that the PCM matrices promoted cellular behaviors and myogenic differentiation of C2C12 myoblasts.Moreover,in vivo experiments demonstrated enhanced muscle remodeling and recovery in mice treated with PCM matrices following VML injury.Mechanistic insights from next-generation sequencing revealed that MXene NPs facilitated protein and ion availability within PCM matrices,leading to elevated intracellular Ca^(2+)levels in myoblasts through the activation of inducible nitric oxide synthase(i NOS)and serum/glucocorticoid regulated kinase 1(SGK1),ultimately promoting myogenic differentiation via the m TOR-AKT pathway.Additionally,upregulated i NOS and increased NO–contributed to myoblast proliferation and fiber fusion,thereby facilitating overall myoblast maturation.These findings underscore the potential of MXene NPs loaded within highly aligned matrices as therapeutic agents to promote skeletal muscle tissue recovery.展开更多
We previously demonstrated that lipopolysaccharide(LPS)injection-induced immune stress could impair muscle growth in weaned piglets,but the precise mechanisms behind this remain elusive.Here,we found that chronic immu...We previously demonstrated that lipopolysaccharide(LPS)injection-induced immune stress could impair muscle growth in weaned piglets,but the precise mechanisms behind this remain elusive.Here,we found that chronic immune stress induced by LPS resulted in a significant reduction of 36.86%in the total muscle mass of piglets at 5 d post-treatment compared with the control group.At 1 d,prior to muscle mass loss,multiple alterations were noted in response to LPS treatment.These included a reduction in the abundance of Bacteroidetes,an increase in serum concentrations of pro-inflammatory cytokines,compromised mitochondrial morphology,and an upregulation in the expression of dynamin-related protein 1(Drp1),a critical protein involved in mitochondrial fission.We highlight a strong negative correlation between Bacteroidetes abundance and the levels of serum pro-inflammatory cytokines,corroborated by in vivo intervention strategies in the musculature of both pig and mouse models.Mechanistically,the effects of Bacteroidetes on inflammation and muscle mass loss may involve the signaling pathway of the tauro-β-muricholic acid-fibroblast growth factor 15.Furthermore,the induction of overexpression of inflammatory cytokines,achieved without LPS treatment through oral administration of recombinant human IL-6(rh IL-6),led to increased levels of circulating cytokines,subsequently causing a decrease in muscle mass.Notably,pre-treatment with Mdivi-1,an inhibitor of Drp-1,markedly attenuated the LPS-induced elevation in reactive oxygen species levels and rescued the associated decline in muscle mass.Collectively,these data indicate that LPS-induced muscle mass loss was linked to the reduction of Bacteroidetes abundance,increased inflammation,and the disruption of mitochondrial morphology.These insights offer promising avenues for the identification of potential therapeutic targets aimed at mitigating muscle mass loss.展开更多
文摘Chronic heart failure （CHF） is a highly prevalent condition among the elderly and is associated with considerable morbidity, institution-alization and mortality. In its advanced stages, CHF is often accompanied by the loss of muscle mass and strength. Sarcopenia is a geriatric syndrome that has been actively studied in recent years due to its association with a wide range of adverse health outcomes. The goal of this review is to discuss the relationship between CHF and sarcopenia, with a focus on shared pathophysiological pathways and treatments. Mal- nutrition, systemic inflammation, endocrine imbalances, and oxidative stress appear to connect sarcopenia and CHF. At the muscular level, alterations of the ubiquitin proteasome system, myostatin signaling, and apoptosis have been described in both sarcopenia and CHF and could play a role in the loss of muscle mass and function. Possible therapeutic strategies to impede the progression of muscle wasting in CHF patients include protein and vitamin D supplementation, structured physical exercise, and the administration of angiotensin-converting enzyme inhibitors and β-blockers. Hormonal supplementation with growth hormone, testosterone, and ghrelin is also discussed as a potential treatment.
文摘Colorectal cancer(CRC)is the third most commonly diagnosed cancer globally and the second cancer in terms of mortality.The prevalence of sarcopenia in patients with CRC ranges between 12%-60%.Sarcopenia comes from the Greek“sarx”for flesh,and“penia”for loss.Sarcopenia is considered a phenomenon of the aging process and precedes the onset of frailty(primary sarcopenia),but sarcopenia may also result from pathogenic mechanisms and that disorder is termed secondary sarcopenia.Sarcopenia diagnosis is confirmed by the presence of low muscle quantity or quality.Three parameters need to be measured:muscle strength,muscle quantity and physical performance.The standard method to evaluate muscle mass is by analyzing the tomographic total cross-sectional area of all muscle groups at the level of lumbar 3rd vertebra.Sarcopenia may negatively impact on the postoperative outcomes of patients with colorectal cancer undergoing surgical resection.It has been described an association between sarcopenia and numerous poor short-term CRC outcomes like increased perioperative mortality,postoperative sepsis,prolonged length of stay,increased cost of care and physical disability.Sarcopenia may also negatively impact on overall survival,disease-free survival,recurrence-free survival,and cancerspecific survival in patients with non-metastatic and metastatic colorectal cancer.Furthermore,patients with sarcopenia seem prone to toxic effects during chemotherapy,requiring dose deescalations or treatment delays,which seems to reduce treatment efficacy.A multimodal approach including nutritional support(dietary intake,high energy,high protein,and omega-3 fatty acids),exercise programs and anabolic-orexigenic agents(ghrelin,anamorelin),could contribute to muscle mass preservation.Addition of sarcopenia screening to the established clinical-pathological scores for patients undergoing oncological treatment(chemotherapy,radiotherapy or surgery)seems to be the next step for the best of care of CRC patients.
基金This work was supported by a grant from The Plastic Surgery Foundation(PSF312406,to Q.Zhang)by the Kyte Fund through MD Anderson’s Department of Plastic Surgery+1 种基金This research was also supported by the NIH through MD Anderson’s Cancer Center Support Grant(P30CA016672)used MD Anderson’s High Resolution Electron Microscopy Facility,Flow Cytometry and Cellular Imaging Core Facility,and Proteomics and Metabolomics Core Facility.
文摘Muscle flaps must have a strong vascular network to support a large tissue volume and ensure successful engraftment.We developed porcine stomach musculofascial flap matrix(PDSF)comprising extracellular matrix(ECM)and intact vasculature.PDSF had a dominant vascular pedicle,microcirculatory vessels,a nerve network,well-retained 3-dimensional(3D)nanofibrous ECM structures,and no allo-or xenoantigenicity.In-depth proteomic analysis demonstrated that PDSF was composed of core matrisome proteins(e.g.,collagens,glycoproteins,proteoglycans,and ECM regulators)that,as shown by Gene Ontology term enrichment analysis,are functionally related to musculofascial biological processes.Moreover,PDSFhuman adipose-derived stem cell(hASC)synergy not only induced monocytes towards IL-10producing M2 macrophage polarization through the enhancement of hASCs’paracrine effect but also promoted the proliferation and interconnection of both human skeletal muscle myoblasts(HSMMs)and human umbilical vein endothelial cells(HUVECs)in static triculture conditions.Furthermore,PDSF was successfully prevascularized through a dynamic perfusion coculture of hASCs and HUVECs,which integrated with PDSF and induced the maturation of vascular networks in vitro.In a xenotransplantation model,PDSF demonstrated myoconductive and immunomodulatory properties associated with the predominance of M2 macrophages and regulatory T cells.In a volumetric muscle loss(VML)model,prevascularized PDSF augmented neovascularization and constructive remodeling,which was characterized by the predominant infiltration of M2 macrophages and significant musculofascial tissue formation.These results indicate that hASCs’integration with PDSF enhances the cells’dual function in immunomodulation and angiogenesis.Owing in part to this PDSF-hASC synergy,our platform shows promise for vascularized muscle flap engineering for VML reconstruction.
基金supported by the National Science Foundation(CBET 1751554)the National Institutes of Health,the Arkansas Integrative Metabolic Research Center(5P20GM139768-02)the Arkansas Biosciences Institute.Any opinions,-ndings,and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the acknowledged funding agencies.
文摘Nicotinamide adenine dinucleotide(NADH)is a cofactor that serves to shuttle electrons during metabolic processes such as glycolysis,the tricarboxylic acid cycle,and oxidative phosphorylation(OXPHOS).NADH is autofluorescent,and itsfluorescence lifetime can be used to infer metabolic dynamics in living cells.Fiber-coupled time-correlated single photon counting(TCSPC)equipped with an implantable needle probe can be used to measure NADH lifetime in vivo,enabling investigation of changing metabolic demand during muscle contraction or tissue regeneration.This study illustrates a proof of concept for point-based,minimally-invasive NADHfluorescence lifetime measurement in vivo.Volumetric muscle loss(VML)injuries were created in the left tibialis anterior(TA)muscle of male Sprague Dawley rats.NADH lifetime measurements were collected before,during,and after a 30 s tetanic contraction in the injured and uninjured TA muscles,which was subsequently-t to a biexponential decay model to yield a metric of NADH utilization(cytoplasmic vs protein-bound NADH,the A11/A22 ratio).On average,this ratio was higher during and after contraction in uninjured muscle compared to muscle at rest,suggesting higher levels of free NADH in contracting and recovering muscle,indicating increased rates of glycolysis.In injured muscle,this ratio was higher than uninjured muscle overall but decreased over time,which is consistent with current knowledge of inflammatory response to injury,suggesting tissue regeneration has occurred.These data suggest that-ber-coupled TCSPC has the potential to measure changes in NADH binding in vivo in a minimally invasive manner that requires further investigation.
基金supported by the National Research Foundation of Korea(NRF)grant funded by the Korean Government(the Ministry of Science and ICT(MSIT))(No.2021R1A2C2006013)the Bio&Medical Technology Development Program of the NRF funded by the Korean government(MSIT)(No.RS-2023-00223591)the Korea Medical Device Development Fund grant funded by the Korean government(the MSIT,the MOTIE,the Ministry of Health and Welfare,the Ministry of Food and Drug Safety)(NTIS Number:9991006781,KMDF_PR_(2)0200901_0108)。
文摘Current therapeutic approaches for volumetric muscle loss(VML)face challenges due to limited graft availability and insufficient bioactivities.To overcome these limitations,tissue-engineered scaffolds have emerged as a promising alternative.In this study,we developed aligned ternary nanofibrous matrices comprised of poly(lactide-co-ε-caprolactone)integrated with collagen and Ti_(3)C_(2)T_(x)MXene nanoparticles(NPs)(PCM matrices),and explored their myogenic potential for skeletal muscle tissue regeneration.The PCM matrices demonstrated favorable physicochemical properties,including structural uniformity,alignment,microporosity,and hydrophilicity.In vitro assays revealed that the PCM matrices promoted cellular behaviors and myogenic differentiation of C2C12 myoblasts.Moreover,in vivo experiments demonstrated enhanced muscle remodeling and recovery in mice treated with PCM matrices following VML injury.Mechanistic insights from next-generation sequencing revealed that MXene NPs facilitated protein and ion availability within PCM matrices,leading to elevated intracellular Ca^(2+)levels in myoblasts through the activation of inducible nitric oxide synthase(i NOS)and serum/glucocorticoid regulated kinase 1(SGK1),ultimately promoting myogenic differentiation via the m TOR-AKT pathway.Additionally,upregulated i NOS and increased NO–contributed to myoblast proliferation and fiber fusion,thereby facilitating overall myoblast maturation.These findings underscore the potential of MXene NPs loaded within highly aligned matrices as therapeutic agents to promote skeletal muscle tissue recovery.
基金supported by the National Natural Science Foundation of China(32372925)the Science and Technology Innovation Program of Hunan Province(2022RC1159)+2 种基金the Changsha Natural Science Funds for Distinguished Young Scholar(kq2009020)the National Key Research and Development Programs of China(2022YFD1300503)the China Agriculture Research System of MOF and MARA(CARS35)。
文摘We previously demonstrated that lipopolysaccharide(LPS)injection-induced immune stress could impair muscle growth in weaned piglets,but the precise mechanisms behind this remain elusive.Here,we found that chronic immune stress induced by LPS resulted in a significant reduction of 36.86%in the total muscle mass of piglets at 5 d post-treatment compared with the control group.At 1 d,prior to muscle mass loss,multiple alterations were noted in response to LPS treatment.These included a reduction in the abundance of Bacteroidetes,an increase in serum concentrations of pro-inflammatory cytokines,compromised mitochondrial morphology,and an upregulation in the expression of dynamin-related protein 1(Drp1),a critical protein involved in mitochondrial fission.We highlight a strong negative correlation between Bacteroidetes abundance and the levels of serum pro-inflammatory cytokines,corroborated by in vivo intervention strategies in the musculature of both pig and mouse models.Mechanistically,the effects of Bacteroidetes on inflammation and muscle mass loss may involve the signaling pathway of the tauro-β-muricholic acid-fibroblast growth factor 15.Furthermore,the induction of overexpression of inflammatory cytokines,achieved without LPS treatment through oral administration of recombinant human IL-6(rh IL-6),led to increased levels of circulating cytokines,subsequently causing a decrease in muscle mass.Notably,pre-treatment with Mdivi-1,an inhibitor of Drp-1,markedly attenuated the LPS-induced elevation in reactive oxygen species levels and rescued the associated decline in muscle mass.Collectively,these data indicate that LPS-induced muscle mass loss was linked to the reduction of Bacteroidetes abundance,increased inflammation,and the disruption of mitochondrial morphology.These insights offer promising avenues for the identification of potential therapeutic targets aimed at mitigating muscle mass loss.
