Muscle Maintenance Research Articles

Abstract 3028: Diabetic Complication Ischemia Triggers Muscle Mass And Muscle Weight Loss By Reducing Mesenchymal Progenitor Cells Population Proliferation

Introduction: Mesenchymal progenitor cells (MPCs), such as myoblasts and fibroadipogenic progenitors (FAPs), and their communications with each other and with immune and vascular cells are responsible for muscle maintenance and regeneration. We hypothesize that in diabetes, loss of muscle mass after induction of hind limb ischemia is mediated by reduction in myoblast proliferation, thereby impairing muscle regeneration. Methods: Ischemic injury was induced in male diabetic (Akita) and littermate Wild Type (WT) mice via unilateral femoral artery ligation (FAL). Gastrocnemius muscle was collected at baseline, 3 and 7 days after surgery for single-cell RNA sequencing (scRNA seq). We identified the different cell populations in clusters, determined differentially-expressed genes, utilized Reactome Pathway Analysis and analyzed the cell cycle progression status and cell-cell interactions. Results: scRNA seq analysis of diabetic mice muscle, but not WT muscle, showed a reduction in MPCs, myoblasts and fibroadipogenic progenitors (FAPs) at 3 days post-FAL vs. baseline. FAPs were identified as two distinct subclusters; FAPs/Lum+ (associated with cell cycle regulation) and FAPs/Prg4+ (associated with extracellular matrix remodeling). We observed a lack of pathways involved in cell cycle progression in myoblasts at 3 days post- FAL in diabetic vs. WT muscle. At day 7 post-FAL, we observed an increased number of cell cycle pathways vs. day 3 post-FAL in diabetic muscle, implying a delayed response in the myoblasts. Cell cycle progression analysis revealed fewer diabetic myoblasts in S/G2M phase, with lower expression of proliferation markers (Mki67, Top2a, Mcm6 and Pcna), but no significant differences were observed in FAP/Lum+ cells. Cell-cell interaction analysis at day 3 post-FAL revealed fewer FAP-myoblast interactions in diabetic muscle, while interactions between either FAPs/myoblasts and myeloid cells were higher. Conclusion: These findings suggest that understanding the network of inter-cellular communications among MPCs, immune and vascular cells, and their roles in reduced myoblast proliferation after ischemia, is critical to identify new therapies to stimulate regeneration in diabetes and peripheral vascular disease.

Prolyl isomerase Pin1 in skeletal muscles contributes to systemic energy metabolism and exercise capacity through regulating SERCA activity

The skeletal muscle is a pivotal organ involved in the regulation of both energy metabolism and exercise capacity. There is no doubt that exercise contributes to a healthy life through the consumption of excessive energy or the release of myokines. Skeletal muscles exhibit insulin sensitivity and can rapidly uptake blood glucose. In addition, they can undergo non-shivering thermogenesis through actions of both the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) and small peptide, sarcolipin, resulting in systemic energy metabolism. Accordingly, the maintenance of skeletal muscles is important for both metabolism and exercise. Prolyl isomerase Pin1 is an enzyme that converts the cis-trans form of proline residues and controls substrate function. We have previously reported that Pin1 plays important roles in insulin release, thermogenesis, and lipolysis. However, the roles of Pin1 in skeletal muscles remains unknown. To clarify this issue, we generated skeletal muscle-specific Pin1 knockout mice.Pin1 deficiency had no effects on muscle weights, morphology and ratio of fiber types. However, they showed exacerbated obesity or insulin resistance when fed with a high-fat diet. They also showed a lower ability to exercise than wild type mice did. We also found that Pin1 interacted with SERCA and elevated its activity, resulting in the upregulation of oxygen consumption. Overall, our study reveals that Pin1 in skeletal muscles contributes to both systemic energy metabolism and exercise capacity.

Dynamic equilibrium of skeletal muscle macrophage ontogeny in the diaphragm during homeostasis, injury, and recovery

The diaphragm is a unique skeletal muscle due to its continuous activation pattern during the act of breathing. The ontogeny of macrophages, pivotal cells for skeletal muscle maintenance and regeneration, is primarily based on two distinct origins: postnatal bone marrow-derived monocytes and prenatal embryonic progenitors. Here we employed chimeric mice to study the dynamics of these two macrophage populations under different conditions. Traditional chimeric mice generated through whole body irradiation showed virtually complete elimination of the original tissue-resident macrophage pool. We then developed a novel method which employs lead shielding to protect the diaphragm tissue niche from irradiation. This allowed us to determine that up to almost half of tissue-resident macrophages in the diaphragm can be maintained independently from bone marrow-derived monocytes under steady-state conditions. These findings were confirmed by long-term (5 months) parabiosis experiments. Acute diaphragm injury shifted the macrophage balance toward an overwhelming predominance of bone marrow (monocyte)-derived macrophages. However, there was a remarkable reversion to the pre-injury ontological landscape after diaphragm muscle recovery. This diaphragm shielding method permits analysis of the dynamics of macrophage origin and corresponding function under different physiological and pathological conditions. It may be especially useful for studying diseases which are characterized by acute or chronic injury of the diaphragm and accompanying inflammation.

Association of short-term changes in HbA1c with body composition and the importance of muscle maintenance in patients with Type 2 diabetes

AimsThis study aimed to investigate the relationship between changes in glucose metabolism and body composition in patients with diabetes. MethodsWe included 380 patients with type 2 diabetes, who underwent bioelectrical impedance analysis, in this longitudinal study. Changes in HbA1c (ΔHbA1c) levels and body composition indices were compared between baseline and 6 months. A multivariate analysis was performed to examine the relationship between ΔHbA1c and changes in body composition. ResultsHbA1c levels were significantly decreased at 6 months (P < 0.01), but there was no significant change in BMI. A linear multiple regression analysis showed that ΔHbA1c was negatively correlated with changes in muscle mass (β = −0.18; P = 0.047) and bone mineral content (β = −0.28; P < 0.001), but there was no significant association between ΔHbA1c levels and a change in body fat percentage. ConclusionsThis study shows a limited association between short-term changes in glucose metabolism and changes in body composition in patients with type 2 diabetes. Therefore, interventions aimed at reducing adiposity may not affect glucose metabolism in the short term, while interventions focused on maintaining or enhancing muscle mass and bone mineral content may play an important role in diabetes management.

Cadherin-dependent adhesion is required for muscle stem cell niche anchorage and maintenance.

Adhesion between stem cells and their niche provides stable anchorage and signaling cues to sustain properties such as quiescence. Skeletal muscle stem cells (MuSCs) adhere to an adjacent myofiber via cadherin-catenin complexes. Previous studies on N- and M-cadherin in MuSCs revealed that although N-cadherin is required for quiescence, they are collectively dispensable for MuSC niche localization and regenerative activity. Although additional cadherins are expressed at low levels, these findings raise the possibility that cadherins are unnecessary for MuSC anchorage to the niche. To address this question, we conditionally removed from MuSCs β- and γ-catenin, and, separately, αE- and αT-catenin, factors that are essential for cadherin-dependent adhesion. Catenin-deficient MuSCs break quiescence similarly to N-/M-cadherin-deficient MuSCs, but exit the niche and are depleted. Combined in vivo, ex vivo and single cell RNA-sequencing approaches reveal that MuSC attrition occurs via precocious differentiation, re-entry to the niche and fusion to myofibers. These findings indicate that cadherin-catenin-dependent adhesion is required for anchorage of MuSCs to their niche and for preservation of the stem cell compartment. Furthermore, separable cadherin-regulated functions govern niche localization, quiescence and MuSC maintenance.

Aging-affiliated post-translational modifications of skeletal muscle myosin affect biochemical properties, myofibril structure, muscle function, and proteostasis.

The molecular motor myosin is post-translationally modified in its globular head, its S2 hinge, and its thick filament domain during human skeletal muscle aging. To determine the importance of such modifications, we performed an integrative analysis of transgenic Drosophila melanogaster expressing myosin containing post-translational modification mimic mutations. We determined effects on muscle function, myofibril structure, and myosin biochemistry. Modifications in the homozygous state decreased jump muscle function by a third at 3 weeks of age and reduced indirect flight muscle function to negligible levels in young flies, with severe effects on flight muscle myofibril assembly and/or maintenance. Expression of mimic mutations in the heterozygous state or in a wild-type background yielded significant, but less severe, age-dependent effects upon flight muscle structure and function. Modification of the residue in the globular head disabled ATPase activity and invitro actin filament motility, whereas the S2 hinge mutation reduced actin-activated ATPase activity by 30%. The rod modification diminished filament formation invitro. The latter mutation also reduced proteostasis, as demonstrated by enhanced accumulation of polyubiquitinated proteins. Overall, we find that mutation of amino acids at sites that are chemically modified during human skeletal muscle aging can disrupt myosin ATPase, myosin filament formation, and/or proteostasis, providing a mechanistic basis for the observed muscle defects. We conclude that age-specific post-translational modifications present in human skeletal muscle are likely to act in a dominant fashion to affect muscle structure and function and may therefore be implicated in degeneration and dysfunction associated with sarcopenia.

Chromatin profiling reveals TFAP4 as a critical transcriptional regulator of bovine satellite cell differentiation

BackgroundSatellite cells are myogenic precursor cells in adult skeletal muscle and play a crucial role in skeletal muscle regeneration, maintenance, and growth. Like embryonic myoblasts, satellite cells have the ability to proliferate, differentiate, and fuse to form multinucleated myofibers. In this study, we aimed to identify additional transcription factors that control gene expression during bovine satellite cell proliferation and differentiation.ResultsUsing chromatin immunoprecipitation followed by sequencing, we identified 56,973 and 54,470 genomic regions marked with both the histone modifications H3K4me1 and H3K27ac, which were considered active enhancers, and 50,956 and 59,174 genomic regions marked with H3K27me3, which were considered repressed enhancers, in proliferating and differentiating bovine satellite cells, respectively. In addition, we identified 1,216 and 1,171 super-enhancers in proliferating and differentiating bovine satellite cells, respectively. Analyzing these enhancers showed that in proliferating bovine satellite cells, active enhancers were associated with genes stimulating cell proliferation or inhibiting myoblast differentiation whereas repressed enhancers were associated with genes essential for myoblast differentiation, and that in differentiating satellite cells, active enhancers were associated with genes essential for myoblast differentiation or muscle contraction whereas repressed enhancers were associated with genes stimulating cell proliferation or inhibiting myoblast differentiation. Active enhancers in proliferating bovine satellite cells were enriched with binding sites for many transcription factors such as MYF5 and the AP-1 family transcription factors; active enhancers in differentiating bovine satellite cells were enriched with binding sites for many transcription factors such as MYOG and TFAP4; and repressed enhancers in both proliferating and differentiating bovine satellite cells were enriched with binding sites for NF-kB, ZEB-1, and several other transcription factors. The role of TFAP4 in satellite cell or myoblast differentiation was previously unknown, and through gene knockdown and overexpression, we experimentally validated a critical role for TFAP4 in the differentiation and fusion of bovine satellite cells into myofibers.ConclusionsSatellite cell proliferation and differentiation are controlled by many transcription factors such as AP-1, TFAP4, NF-kB, and ZEB-1 whose roles in these processes were previously unknown in addition to those transcription factors such as MYF5 and MYOG whose roles in these processes are widely known.

Control of muscle satellite cell function by specific exercise-induced cytokines and their applications in muscle maintenance.

Exercise is recognized to play an observable role in improving human health, especially in promoting muscle hypertrophy and intervening in muscle mass loss-related diseases, including sarcopenia. Recent rapid advances have demonstrated that exercise induces the release of abundant cytokines from several tissues (e.g., liver, muscle, and adipose tissue), and multiple cytokines improve the functions or expand the numbers of adult stem cells, providing candidate cytokines for alleviating a wide range of diseases. Muscle satellite cells (SCs) are a population of muscle stem cells that are mitotically quiescent but exit from the dormancy state to become activated in response to physical stimuli, after which SCs undergo asymmetric divisions to generate new SCs (stem cell pool maintenance) and commit to later differentiation into myocytes (skeletal muscle replenishment). SCs are essential for the postnatal growth, maintenance, and regeneration of skeletal muscle. Emerging evidence reveals that exercise regulates muscle function largely via the exercise-induced cytokines that govern SC potential, but this phenomenon is complicated and confusing. This review provides a comprehensive integrative overview of the identified exercise-induced cytokines and the roles of these cytokines in SC function, providing a more complete picture regarding the mechanism of SC homeostasis and rejuvenation therapies for skeletal muscle.

Falcon gut microbiota is shaped by diet and enriched in Salmonella.

The gut microbiome is increasingly being appreciated as a master regulator of animal health. However, avian gut microbiome studies commonly focus on birds of economic importance and the gut microbiomes of raptors remain underexplored. Here we examine the gut microbiota of 29 captive falcons-raptors of historic importance-in the context of avian evolution by sequencing the V4 region of the 16S rRNA gene. Our results reveal that evolutionary histories and diet are significantly associated with avian gut microbiota in general, whereas diet plays a major role in shaping the falcon gut microbiota. Multiple analyses revealed that gut microbial diversity, composition, and relative abundance of key diet-discriminating bacterial genera in the falcon gut closely resemble those of carnivorous raptors rather than those of their closest phylogenetic relatives. Furthermore, the falcon microbiota is dominated by Firmicutes and contains Salmonella at appreciable levels. Salmonella presence was associated with altered functional capacity of the falcon gut microbiota as its abundance is associated with depletion of multiple predicted metabolic pathways involved in protein mass buildup, muscle maintenance, and enrichment of antimicrobial compound degradation, thus increasing the pathogenic potential of the falcon gut. Our results point to the necessity of screening for Salmonella and other human pathogens in captive birds to safeguard both the health of falcons and individuals who come in contact with these birds.

Postnatal Pdzrn3 deficiency causes acute muscle atrophy without alterations in endplate morphology

PDZ domain-containing RING finger family protein 3 (PDZRN3) is expressed in various tissues, including the skeletal muscle. Although PDZRN3 plays a crucial role in the terminal differentiation of myoblasts and synaptic growth/maturation in myogenesis, the role of this molecule in postnatal muscles is completely unknown despite its lifelong expression in myofibers. In this study, we aimed to elucidate the function of PDZRN3 in mature myofibers using myofiber-specific conditional knockout mice. After tamoxifen injection, PDZRN3 deficiency was confirmed in both fast and slow myofibers of Myf6-CreERT2; Pdzrn3flox/flox (Pdzrn3mcKO) mice. Transcriptome analysis of the skeletal muscles of Pdzrn3mcKO mice identified differentially expressed genes, including muscle atrophy-related genes such as Smox, Amd1/2, and Mt1/2, suggesting that PDZRN3 is involved in the homeostatic maintenance of postnatal muscles. PDZRN3 deficiency caused muscle atrophy, predominantly in fast-twitch (type II) myofibers, and reduced muscle strength. While myofiber-specific PDZRN3 deficiency did not influence endplate morphology or expression of neuromuscular synaptic formation-related genes in postnatal muscles, indicating that the relationship between PDZRN3 and neuromuscular junctions might be limited during muscle development. Considering that the expression of Pdzrn3 in skeletal muscles was significantly lower in aged mice than in mature adult mice, we speculated that the PDZRN3-mediated muscle maintenance system might be associated with the pathophysiology of age-related muscle decline, such as sarcopenia.

DAG1 haploinsufficiency is associated with sporadic and familial isolated or pauci-symptomatic hyperCKemia.

DAG1 encodes for dystroglycan, a key component of the dystrophin-glycoprotein complex (DGC) with a pivotal role in skeletal muscle function and maintenance. Biallelic loss-of-function DAG1 variants cause severe muscular dystrophy and muscle-eye-brain disease. A possible contribution of DAG1 deficiency to milder muscular phenotypes has been suggested. We investigated the genetic background of twelve subjects with persistent mild-to-severe hyperCKemia to dissect the role of DAG1 in this condition. Genetic testing was performed through exome sequencing (ES) or custom NGS panels including various genes involved in a spectrum of muscular disorders. Histopathological and Western blot analyses were performed on muscle biopsy samples obtained from three patients. We identified seven novel heterozygous truncating variants in DAG1 segregating with isolated or pauci-symptomatic hyperCKemia in all families. The variants were rare and predicted to lead to nonsense-mediated mRNA decay or the formation of a truncated transcript. In four cases, DAG1 variants were inherited from similarly affected parents. Histopathological analysis revealed a decreased expression of dystroglycan subunits and Western blot confirmed a significantly reduced expression of beta-dystroglycan in muscle samples. This study supports the pathogenic role of DAG1 haploinsufficiency in isolated or pauci-symptomatic hyperCKemia, with implications for clinical management and genetic counseling.

Satellite cells in the growth and maintenance of muscle.

Embryonic skeletal muscle growth is contingent upon a population of somite derived satellite cells, however, the contribution of these cells to early postnatal skeletal muscle growth remains relatively high. As prepubertal postnatal development proceeds, the activity and contribution of satellite cells to skeletal muscle growth diminishes. Eventually, at around puberty, a population of satellite cells escapes terminal commitment, continues to express the paired box transcription factor Pax7, and reside in a quiescent state orbiting the myofiber periphery adjacent to the basal lamina. After adolescence, some satellite cell contributions to muscle maintenance and adaptation occur, however, their necessity is reduced relative to embryonic, early postnatal, and prepubertal growth.

YAP/TAZ as Molecular Targets in Skeletal Muscle Atrophy and Osteoporosis.

Skeletal muscles and bones are closely connected anatomically and functionally. Age-related degeneration in these tissues is associated with physical disability in the elderly and significantly impacts their quality of life. Understanding the mechanisms of age-related musculoskeletal tissue degeneration is crucial for identifying molecular targets for therapeutic interventions for skeletal muscle atrophy and osteoporosis. The Hippo pathway is a recently identified signaling pathway that plays critical roles in development, tissue homeostasis, and regeneration. The Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are key downstream effectors of the mammalian Hippo signaling pathway. This review highlights the fundamental roles of YAP and TAZ in the homeostatic maintenance and regeneration of skeletal muscles and bones. YAP/TAZ play a significant role in stem cell function by relaying various environmental signals to stem cells. Skeletal muscle atrophy and osteoporosis are related to stem cell dysfunction or senescence triggered by YAP/TAZ dysregulation resulting from reduced mechanosensing and mitochondrial function in stem cells. In contrast, the maintenance of YAP/TAZ activation can suppress stem cell senescence and tissue dysfunction and may be used as a basis for the development of potential therapeutic strategies. Thus, targeting YAP/TAZ holds significant therapeutic potential for alleviating age-related muscle and bone dysfunction and improving the quality of life in the elderly.

Muscle Progenitor Cell Fusion in the Maintenance of Skeletal Muscle.

Skeletal muscle possesses a resident, multipotent stem cell population that is essential for its repair and maintenance throughout life. Here I highlight the role of this stem cell population in muscle repair and regeneration and review the genetic control of the process; the mechanistic steps of activation, migration, recognition, adhesion, and fusion of these cells; and discuss the novel recognition of the membrane signaling that coordinates myogenic cell-cell fusion, as well as the identification of a two-part fusogen system that facilitates it.

The roles of sex hormones in the pathophysiology of age-related sarcopenia and frailty.

Sarcopenia is an age-related condition characterized by a progressive and systemic decline in skeletal muscle mass, quality, and strength. The incidence of sarcopenia contains sex-specific aspects, indicating the contribution of sex hormones to its pathophysiology. This review focuses on changing trends in sarcopenia, discusses alterations in definitions and diagnostic criteria, and emphasizes the association between sarcopenia and sex hormones. A literature search was performed on PubMed for related articles published between 1997 and December 2023 using appropriate keywords. Advances in research have emphasized the significance of muscle quality and strength over muscle mass, resulting in new diagnostic criteria for sarcopenia. Androgens demonstrated anabolic effects on skeletal muscles and played a significant role in the pathophysiology of sarcopenia. In clinical settings, androgen replacement therapy has exhibited certain positive outcomes for treating sarcopenia, despite concerns about potential side effects. Conversely, estrogen is involved in skeletal muscle maintenance, but the detailed mechanisms remain unclear. Moreover, results regarding the clinical application of estrogen replacement therapy for treating sarcopenia remained inconsistent. The elucidation of molecular mechanisms that involve sex hormones is eagerly awaited for novel therapeutic interventions for sarcopenia.

HEMOPEXIN’S RELATIONSHIP WITH MUSCLE QUALITY AND COGNITIVE FUNCTION IN OLDER ADULTS WITH COGNITIVE IMPAIRMENT

Abstract The imminent increase in Alzheimer’s disease (AD) and dementia increases the need for effective prevention strategies. Increasig attention has been paid to exercise as a prevention strateg to promote cognitive health. Recently, the link between hemopexin which is secreted by atrophied skeletal muscle and cognitive function maintenance has been studied, but evidence remains inconclusive.This study examined the relationship between hemopexin, muscle mass, muscle quality (Phase Angle, PhA), and cognitive function (measured by Mini-Mental State Examination) among 377 cognitively impaired older adults (mean age = 83.5 years).TANITA (MC-780A-N) was used to measure body composition. The concentration of hemopexin in human plasma samples was measured using the HPX (Human) ELISA Kit (KA0481). In Pearson correlation analysis, hemopexin showed no significant correlation with muscle mass, quality, or cognitive function. Multivariate regression analysis revealed that lower PhA is significantly associated with poorer cognitive function (t-value=2.012, p&amp;lt; 0.05), but hemopexin and muscle mass were not significant. An interaction analysis indicated that the relationship between hemopexin and muscle quality was modified by sex (t-value=2.052, p&amp;lt; 0.05). In the multivariate analysis for females, hemopexin correlated negatively with muscle quality (t-value=-2.128, p&amp;lt; 0.05). This study shows that hemopexin, though not affecting cognitive function or muscle mass directly, may impact muscle quality, especially considering the link between AD in older women and atrophied muscle with hemopexin secretion. Hence, interventions focused on muscle quality might improve cognitive function in older individuals with cognitive impairment, possibly preventing dementia onset. Further studies are warranted to solidify these connections.

Pax7 reporter mouse models: a pocket guide for satellite cell research.

Since their discovery, satellite cells have showcased their need as primary contributors to skeletal muscle maintenance and repair. Satellite cells lay dormant, but when needed, activate, differentiate, fuse to fibres and self-renew, that has bestowed satellite cells with the title of muscle stem cells. The satellite cell specific transcription factor Pax7 has enabled researchers to develop animal models against the Pax7 locus in order to isolate and characterise satellite cell-mediated events. This review focuses specifically on describing Pax7 reporter mouse models. Here we describe how each model was generated and the key findings obtained. The strengths and limitations of each model are also discussed. The aim is to provide new and current satellite cell enthusiasts with a basic understanding of the available Pax7 reporter mice and hopefully guide selection of the most appropriate Pax7 model to answer a specific research question.

The neuronal nitric oxide synthase expression increases during satellite cell-derived primary myoblasts differentiation.

Theneuronal nitric oxide synthase (nNOS; encoded byNOS1)-derivednitric oxide (NO) plays an important role in maintaining skeletal muscle mass. In adult skeletal muscle, nNOS localizes to the cell membrane, cytosol, and nucleus, and regulates muscle hypertrophy and atrophy in various subcellular fractions.However, its role in muscle stem cells (also known as muscle satellite cells), which provide myonuclei for postnatal muscle growth, maintenance, and regeneration, remains unclear. The present study aimed to determinenNOS expression in muscle satellite cell-derived primary myoblasts during differentiation and its DNA methylation levels, an epigenetic modification that controls gene expression. Undifferentiated and differentiated satellite cell-derived primary myoblasts were found to express nNOS. Immunohistochemical analysis revealed that nNOS colocalized with Pax7 (satellite cell marker) only in the undifferentiated myoblasts. Furthermore, nNOS immunoreactivity spread to the cytosol of Pax7-negative differentiated myotube-like cells. Thelevel of Nos1µmRNA, the main isoform of skeletal muscle nNOS, was increased in differentiated satellite cell-derived primary myoblasts compared to that in the undifferentiated cells. However,Nos1methylation levelsremained unchangedduring differentiation.These findings suggest that nNOS induction and the appropriate transition of its subcellular localization may contribute to muscle differentiation.

A red emissive covalently bonded graphene quantum dot-Tetraaminophenylporphyrin hybrid as a probe for the sensing of L-proline

L-Proline, the exclusive secondary amino acid with proteinogenic properties, is a vital contributor to body metabolism and the maintenance of muscle repairs, playing a pivotal role in numerous physiological processes in the human body. However, the current understanding of proline sensing is limited. In this study, we have used Tetraaminophenylporphyrin (TAPP) covalently functionalized graphene quantum dot (GQD) as a probe for the selective and sensitive detection of L-Proline. Analytical studies carried out under the optimized conditions reveal a good linear range of 9.8×10−5 M to 3.5×10−3 M with 1.6×10−7 M limit of detection. Photophysical studies reveal a ground state complex formation between the probe and proline which is responsible for the turn-off behaviour. This is not present in the case of the individual components GQD and TAPP separately which highlights the importance of covalent functionalization. The stabilization energy of the complex between the probe and different aminoacids and the corresponding hydrogen bond distances between these two moieties were calculated theoretically using density functional theory. This corroborates the enhanced stability of complex formation and the selectivity of probe towards proline compared to other aminoacids. The practical utility of the developed probe for the detection of proline in real samples like commercial milk and artificial urine is also demonstrated by spike recovery analysis which results in a recovery percent and RSD values within the acceptable limit.

Characterization of Anthropometric Changes in Patients with Relapsed/Refractory Myeloma Treated with BCMA Bispecific Antibody Teclistamab

Introduction: Cancer-associated cachexia is associated with poor survival rates in several cancer types. Multiple Myeloma (MM) preferentially occurs in the elderly and is the most common cancer that causes lytic bone metastasis causing bone pain, fractures, mobility limitations, and falls. Cachexia is projected to be common in myeloma but has not been fully studied. Myeloma treatments including corticosteroids, radiation and alkylators cause muscle loss, while novel immunotherapy is tumor-specific but their impact on cachexia is unknown. We characterize the changes in body composition in patients with relapsed/refractory myeloma treated with BCMA bispecific antibody teclistamab and determine the association between body composition with treatement response and overall survival. Methods: 49 MM patients treated with teclistamab between 2000 and 2021 were included. All were with relapsed/refractory disease after &amp;gt; 4 lines of therapy and received an approved dose and schedule of teclistamab. The response assessment was according to IMWG criteria. Body weight, body mass index (BMI), tumor burden, and organ function were assessed at baseline and post-treatment. Standard-of-care abdominopelvic CT or PET/CT scans at baseline and at last known follow up were analyzed with Data Analysis Facilitation Suite (DAFS) software to quantify skeletal muscle (SKM), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT). Differences between groups were tested using the χ 2 test or paired t-test. Progression free survival (PFS) and overall survival (OS) from the start of teclistamab to progression and death or last follow-up, respectively, were analyzed by the Kaplan-Meier method. Comparisons were made with the log-rank test. Results: Patient characteristics are detailed in Table 1. Based on the WHO definition, 2% were underweight, 16% were normal weight, 19% were overweight and 13% were obese, at baseline. The baseline mean SKM was 105.6 ± 27.8 (Male 122.0 ± 25.3, female 93.4 ± 23.5). SAT and VAT varied widely. Median SAT was 196.5 (range 48.3-558.6), and median VAT was 136.6 (33.09-448.1). Of 32 patients in the obese group, 16 (50%) patients had SKM that was below the mean SKM of the group. Baseline SAT and VAT, but not SKM were correlated with BMI. Twenty-seven of the 49 patients had paired imaging. The absolute changes in skeletal muscle and adipose tissue compartments are shown in Table 2. A majority of patients had a decline in SKM, SAT and VAT post-treatment: mean SKM decrease was 8.9 cm 2 ( p ≤ 0.01), mean SAT decreased 24.3 cm 2 ( p = 0.02) and mean VAT decreased 27.4 cm 2 ( p = 0.03), while BMI and weight were unchanged. Nineteen of 27 (70%) subjects responded to therapy. The changes in SKM, VAT, and SAT loss did not differ significantly between responders and non-responders. 38.8% of patients (19/49) had died by the end of the follow-up. Median follow-up duration was 2.8 years, overall survival was 1.7 years and PFS was 0.9 years. Baseline SKM, SAT, and VAT did not correlate with PFS or OS, but a decline in SMK significantly correlated with a shorter OS (p=0.04); 7/18 patients with decreased SKM and 2/9 patients with unchanged or increased SKM died. Response correlated strongly with overall survival (p=0.002). Conclusions: Body composition analysis of standard CT images may provide clinically relevant information for patients with advanced myeloma. Sarcopenia was common despite high BMI, and a further decline in skeletal muscle mass correlated with shorter survival, regardless of response to tumor-specific immunotherapy. Anthropometric changes should be validated in larger patient cohorts and included in future clinical trials. Further efforts should focus on the maintenance of muscle and visceral adipose tissue in this patient population.