Age-related Muscle Dysfunction Research Articles

The Impact of Aging and Biological Sex on Diaphragm Hyperemia and Blood Flow Distribution

INTRODUCTION: Age-related respiratory muscle dysfunction (i.e., the diaphragm) diminishes physical capacity and increases the susceptibility to respiratory failure. The diaphragm dysfunction associated with old age is characterized by decreased diaphragm muscle mass and strength, and increased fatiguability. While inadequate perfusion and diminished microvascular function are well recognized to play a central role in age-related peripheral skeletal muscle dysfunction, the impact of aging on diaphragm hyperemia and blood flow distribution, and whether sex differences exist, has not been investigated. METHODS: Young (Y; 4-6 months) and Old (O; 22-24 months) Fischer 344 rats (n=34) were divided into four groups: 1) Young female (YF; n=8), 2) Young male (YM; n=8), 3) Old female (OF; n=9), and 4) Old male (OM; n=9). Fluorescent microspheres were used to assess bulk and regional diaphragm blood flow at rest and during electrically-induced 1Hz contractions. RESULTS: There were no age-related or sex differences in quiescent diaphragm blood flow (BF) or vascular conductance (VC) ( P>0.05). Age-related differences during 1Hz contractions: The increase in total diaphragm BF was significantly lower in OM (98 ± 11 ml/min/100g) compared to YM (141 ± 7 ml/min/100g; p<0.05). Total and regional diaphragm BF was not different in F rats ( P>0.05); however, medial costal diaphragm VC was decreased in OF (1.2 ± 0.1 ml/mmHg/min/100g) compared to YF (1.8 ± 0.2 ml/mmHg/min/100g; p<0.05). Sex differences during 1Hz contractions: Total diaphragm BF and VC were similar in YF and YM ( P > 0.05). While both ventral and medial costal diaphragm BF responses were not different between YF and YM, dorsal costal diaphragm BF was higher in YF (144 ± 27 ml/min/100g) versus YM (84 ± 11 ml/min/100g; p<0.05). Total and regional (ventral, medial, and dorsal costal) diaphragm BF was significantly higher in OF compared to OM ( p<0.05). CONCLUSION: These data demonstrate that aging impaired the ability of the diaphragm to augment BF in response to contractile activity in M rats and decreased medial costal diaphragm VC during contractions in F rats with no significant effect on diaphragmatic hyperemia. In regards to sex differences, these data suggest that both YF and OF may have a greater regional recruitment of the diaphragm compared to YM and OM. The data herein provide a putative mechanism for age-related diaphragm contractile dysfunction and future studies are needed to investigate the impact of aging and biological sex on diaphragm vascular function. National Institute of Aging 1R15AG078060, Ruth L. Kirschstein National Research Service Awards from the National Heart, Lung, and Blood Institute 1F31HL167618-01 and 1F31HL170643-01, and Sustained Momentum for Investigators with Laboratories Established (SMILE) Grants at Kansas State University. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Polygonatum sibiricum polysaccharide ameliorates skeletal muscle aging via mitochondria-associated membrane-mediated calcium homeostasis regulation

BackgroundSarcopenia, an age-related disease, is characterized by a gradual loss of muscle mass, strength, and function. It has been linked to abnormal organelle function in myotubes, including the mitochondria and endoplasmic reticulum (ER). Recent studies revealed that mitochondria-associated membranes (MAM), the sites connecting mitochondria and the ER, may be implicated in skeletal muscle aging. In this arena, the potential of Polygonatum sibiricum polysaccharide (PSP) emerges as a beacon of hope. PSP, with its remarkable antioxidant and anti-senescence properties, is on the cusp of a therapeutic revolution, offering a promising strategy to mitigate the impacts of sarcopenia. PurposeThe objective of this research is to explore the effects of PSP on age-related muscle dysfunction and the underlying mechanisms involved both in vivo and in vitro. MethodsIn this investigation, we used in vitro experiments using D-galactose (D-gal)-induced aging in C2C12 myotubes and in vivo experiments on aged mice. Key indices were assessed, including reactive oxygen species (ROS) levels, mitochondrial function, the expression of aging-related markers, and the key proteins of mitochondria and MAM fraction. Differentially expressed genes (DEGs) related to mitochondria and ER were identified, and bioinformatic analyses were performed to explore underlying mechanisms. Muscle mass and function were determined to evaluate the quantity and quality of skeletal muscle in vivo. ResultsPSP treatment effectively mitigated oxidative stress and mitochondrial malfunction caused by D-gal in C2C12 myotubes, preserving mitochondrial fitness and reducing MAM formation. Besides, PSP attenuated D-gal-induced increases in Ca2+ concentrations intracellularly by modulating the calcium-related proteins, which were also confirmed by gene ontology (GO) analysis of DEGs. In aged mice, PSP increased muscle mass and improved grip strength, hanging time, and other parameters while reducing ROS levels and increasing antioxidant enzyme activities in skeletal muscle tissue. ConclusionPSP offers protection against age-associated muscle impairments. The proposed mechanism suggests that modulation of calcium homeostasis via regulation of the MAM results in a favorable functional outcome during skeletal muscle aging. The results of this study highlight the prospect of PSP as a curative intervention for sarcopenia and affiliated pathological conditions, warranting further investigation.

Inhibition of CERS1 in skeletal muscle exacerbates age-related muscle dysfunction.

Age-related muscle wasting and dysfunction render the elderly population vulnerable and incapacitated, while underlying mechanisms are poorly understood. Here, we implicate the CERS1 enzyme of the de novo sphingolipid synthesis pathway in the pathogenesis of age-related skeletal muscle impairment. In humans, CERS1 abundance declines with aging in skeletal muscle cells and, correlates with biological pathways involved in muscle function and myogenesis. Furthermore, CERS1 is upregulated during myogenic differentiation. Pharmacological or genetic inhibition of CERS1 in aged mice blunts myogenesis and deteriorates aged skeletal muscle mass and function, which is associated with the occurrence of morphological features typical of inflammation and fibrosis. Ablation of the CERS1 orthologue lagr-1 in Caenorhabditis elegans similarly exacerbates the age-associated decline in muscle function and integrity. We discover genetic variants reducing CERS1 expression in human skeletal muscle and Mendelian randomization analysis in the UK biobank cohort shows that these variants reduce muscle grip strength and overall health. In summary, our findings link age-related impairments in muscle function to a reduction in CERS1, thereby underlining the importance of the sphingolipid biosynthesis pathway in age-related muscle homeostasis.

Inhibition of CERS1 in skeletal muscle exacerbates age-related muscle dysfunction

Age-related muscle wasting and dysfunction render the elderly population vulnerable and incapacitated, while underlying mechanisms are poorly understood. Here, we implicate the CERS1 enzyme of the de novo sphingolipid synthesis pathway in the pathogenesis of age-related skeletal muscle impairment. In humans, CERS1 abundance declines with aging in skeletal muscle cells and, correlates with biological pathways involved in muscle function and myogenesis. Furthermore, CERS1 is upregulated during myogenic differentiation. Pharmacological or genetic inhibition of CERS1 in aged mice blunts myogenesis and deteriorates aged skeletal muscle mass and function, which is associated with the occurrence of morphological features typical of inflammation and fibrosis. Ablation of the CERS1 orthologue lagr-1 in Caenorhabditis elegans similarly exacerbates the age-associated decline in muscle function and integrity. We discover genetic variants reducing CERS1 expression in human skeletal muscle and Mendelian randomization analysis in the UK biobank cohort shows that these variants reduce muscle grip strength and overall health. In summary, our findings link age-related impairments in muscle function to a reduction in CERS1, thereby underlining the importance of the sphingolipid biosynthesis pathway in age-related muscle homeostasis.

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.

Sphingomyelinase as modulator of neuromuscular transmission via presynaptic mechanism

Secretory sphingomyelinases are released in response to various types of stress stimuli, including inflammation [1]. Excessive activity and release of these enzymes can be pathological and accelerate age-related neurological changes, neuroinflammation, neurodegenerative disorders, and muscle dysfunction [1–3]. In contrast, sphingomyelinases were detected in areas close to exocytosis sites and dendritic spines, and their inhibition reduced synaptic transmission at both the presynaptic and postsynaptic levels in hippocampal synapses. Deficiency of acid sphingomyelinase results in neurodegenerative Niemann–Pick disease type A. Knockouts of neutral sphingomyelinases in model mice cause motor defects and disorders that resemble the Alzheimer’s disease phenotype [1, 2]. These findings suggest the existence of a mechanism regulating synaptic transmission, which is dependent on sphingomyelinases. In this study, we examined the impact of neutral sphingomyelinase on neurotransmission in mouse diaphragm muscles using microelectrode recordings of postsynaptic responses, exo-endocytic FM dyes, and fluorescent probes sensitive to membrane properties. The researchers discovered that adding sphingomyelinase at a low concentration (0.01 u/ml) for 15 minutes causes disruption of the lipid packaging of selectively synaptic membranes. This disruption leads to ceramide accumulation, a decrease in staining with Alexa Fluor 488 cholera toxin subunit B conjugate (a marker of GM1 ganglioside cluster), and a shift to the green part of the F2N12S fluorescence spectrum (an indicator of the expansion of the lipid-disordered phase). Increased fluorescence of 22-NBD-cholesterol, indicating an increase in membrane fluidity, and enhanced incorporation of exogenous ceramide into the outer monolayer were observed in the synaptic membranes. Increasing sphingomyelinase concentration to 0.1 u/ml intensifies changes in synaptic membranes and leads to corresponding alterations in membrane properties in muscle fiber plasmalemma. Subsequent experiments used a synapse-specific effect on membrane properties by applying sphingomyelinase at a low concentration for 15 minutes. The application of sphingomyelinase did not alter the amplitude and temporal parameters of miniature postsynaptic responses or the resting membrane potential. Additionally, sphingomyelinase (0.01 u/ml) did not change spontaneous secretion and evoked neurotransmitter release in response to single stimuli. However, the activity of sphingomyelinase led to a notable increase in the release of neurotransmitters and the rate of exocytotic unloading of FM dye from synaptic vesicles during nerve stimulation at 10, 20, and 70 Hz frequencies. The effect of sphingomyelinase on neurotransmission potentiation was irreversible and more significant at 10 Hz activity. Experiments involving intermittent nerve stimulation with short bursts of 60 stimuli each at 10 or 20 Hz frequencies, along with brief 0.5-second rest intervals, indicated that sphingomyelinase elevated the short-term facilitation of neurotransmitter release at the onset of each subsequent episode at 10 Hz (but not at 20 Hz) stimulation. Experiments with a combination of electrophysiological detection of evoked postsynaptic responses, monitoring of exocytotic release of the FM1-43 dye, and the use of FM1-43 fluorescence quencher that penetrates through the fusion pores have demonstrated that a significant portion of synaptic vesicles release the neurotransmitter through the transient fusion pore (kiss-and-run mechanism) during high-frequency (70 Hz) activity [4, 5]. Treatment with sphingomyelinase inhibited the neurotransmitter release pathway. As a consequence, the majority of neurosecretion events went through exocytosis, completely incorporating the vesicular membrane into the presynaptic membrane. Sphingomyelin in the membranes of presynaptic and synaptic vesicles is believed to have varying functions in regulating neurotransmitter release. To investigate this theory, we stimulated the exo-endocytosis processes of synaptic vesicles using sphingomyelinase, which provided access to the synaptic vesicle membranes. Under these circumstances, the enhancing impact of sphingomyelinase on neurotransmitter release and FM1-43 exocytosis rate were notably inhibited. Based on the obtained data, we hypothesize that sphingomyelinase disrupts the integrity of lipid rafts and selectively forms ceramide accumulations in synaptic membranes within the muscles at low concentrations. This ultimately leads to an increase in the mobilization of synaptic vesicles towards exocytosis sites during 10–70 Hz activity. Presumably, the synaptic vesicles from a distinct pool, which predominantly mediates the neurotransmission at a frequency of 10 Hz, are the most actively involved in exocytosis under these circumstances. Sphingomyelinase modifies membrane properties and can inhibit the release of neurotransmitters through the fusion pore during high-frequency activity, redirecting exocytosis towards the complete fusion pathway. Hydrolysis of sphingomyelin in both plasma and synaptic vesicle membranes reduces the stimulatory effects of sphingomyelinase, indicating a contrasting role of sphingomyelin in presynaptic and vesicular membranes for controlling neurotransmitter release [5].

Vitamin D3 Exerts Beneficial Effects on C2C12 Myotubes through Activation of the Vitamin D Receptor (VDR)/Sirtuins (SIRT)1/3 Axis.

The onset of sarcopenia is associated with a decline in vitamin D receptor (VDR) expression, wherein reduced VDR levels contribute to muscle atrophy, while heightened expression promotes muscle hypertrophy. Like VDR, the age-related decline in protein deacetylase sirtuin (SIRT) expression is linked to the development of sarcopenia and age-related muscle dysfunction. This study aimed to investigate whether the VDR agonist 1,25-dihydroxyvitamin D3 (1,25VD3) exerts beneficial effects on muscles through interactions with sirtuins and, if so, the underlying molecular mechanisms. Treatment of 1,25VD3 in differentiating C2C12 myotubes substantially elevated VDR, SIRT1, and SIRT3 expression, enhancing their differentiation. Furthermore, 1,25VD3 significantly enhanced the expression of key myogenic markers, including myosin heavy chain (MyHC) proteins, MyoD, and MyoG, and increased the phosphorylation of AMPK and AKT. Conversely, VDR knockdown resulted in myotube atrophy and reduced SIRT1 and SIRT3 levels. In a muscle-wasting model triggered by IFN-γ/TNF-α in C2C12 myotubes, diminished VDR, SIRT1, and SIRT3 levels led to skeletal muscle atrophy and apoptosis. 1,25VD3 downregulated the increased expression of muscle atrophy-associated proteins, including FoxO3a, MAFbx, and MuRF1 in an IFN-γ/TNF-α induced atrophy model. Importantly, IFN-γ/TNF-α significantly reduced the mtDNA copy number in the C2C12 myotube, whereas the presence of 1,25VD3 effectively prevented this decrease. These results support that 1,25VD3 could serve as a potential preventive or therapeutic agent against age-related muscle atrophy by enhancing the VDR/SIRT1/SIRT3 axis.

The animal protein hydrolysate attenuates sarcopenia via the muscle-gut axis in aged mice

Age-related muscle loss and dysfunction, sarcopenia, is a common condition that results in poor quality of life in the elderly. Protein supplementation is a potential strategy for preventing sarcopenia and increasing muscle synthesis, but the effectiveness of protein type and level in improving sarcopenia is not well understood. In this study, we compared animal protein hydrolysate (APH), which has a high protein digestibility-corrected amino acid score (PDCAAS) and low molecular weight, with casein as a control group to investigate the effects and mechanisms of sarcopenia improvement, with a particular focus on the gut-muscle axis. APH supplementation improved age-related declines in muscle mass, grip strength, hind leg thickness, muscle protein level, muscle fiber size, and myokine levels, compared to the control group. In particular, levels of plasma cortisol, muscle lipids, and muscle collagen were markedly reduced by APH supplements in the aged mice. Furthermore, APH efficiently recovered the concentration of total SCFAs including acetic, propionic, and isovaleric acids decreased in aged mice. Finally, APH induced changes in gut microbiota and increased production of SCFAs, which were positively correlated with muscle protein level and negatively correlated with pro-inflammatory cytokines. In conclusion, APH can help to inhibit age-related sarcopenia by increasing muscle synthesis, inhibiting muscle breakdown, and potentially modulating the gut-muscle axis.

Sphingolipids accumulate in aged muscle, and their reduction counteracts sarcopenia.

Age-related muscle dysfunction and sarcopenia are major causes of physical incapacitation in older adults and currently lack viable treatment strategies. Here we find that sphingolipids accumulate in mouse skeletal muscle upon aging and that both genetic and pharmacological inhibition of sphingolipid synthesis prevent age-related decline in muscle mass while enhancing strength and exercise capacity. Inhibition of sphingolipid synthesis confers increased myogenic potential and promotes protein synthesis. Within the sphingolipid pathway, we show that accumulation of dihydroceramides is the culprit disturbing myofibrillar homeostasis. The relevance of sphingolipid pathways in human aging is demonstrated in two cohorts, the UK Biobank and Helsinki Birth Cohort Study in which gene expression-reducing variants of SPTLC1 and DEGS1 are associated with improved and reduced fitness of older individuals, respectively. These findings identify sphingolipid synthesis inhibition as an attractive therapeutic strategy for age-related sarcopenia and co-occurring pathologies.

Adiponectin receptors activation performs dual effects on regulating myogenesis and adipogenesis of young and aged muscle satellite cells.

Skeletal muscle mass and function deteriorate with ageing. Adiponectin receptors (APNrs), mainly activated by adiponectin, participate in various physiological activities and have varying signalling pathways at different ages. This study aimed to explore whether discrepant performance exists in APNr activation regulating young and aged muscle satellite cells (MUSCs) and whether age-related muscle dysfunction could be alleviated upon APNr activation. The gastrocnemius muscle phenotype was observed in male mice aged 2 and 18 months. An APNr agonist (AdipoRon) was used in vitro and in vivo to investigate the changes in cell biological behaviours and whether muscle dysfunction could be retarded after APNr activation. Aged mice exhibited decreased muscle mass and increased fat infiltration. APNr activation inhibited C2C12 cells and young MUSCs (YMUSCs) proliferation but showed no obvious effect on aged MUSCs (AMUSCs). Moreover, APNr activation inhibited the migration of both YMUSCs and AMUSCs. Interestingly, APNr activation hampered the myogenic differentiation but advanced the adipogenic differentiation of YMUSCs, yet exact opposite results were presented in AMUSCs. It was demonstrated that Wnt and PI3K signalling pathways may mediate the phenotypic differences. Furthermore, in vivo experiments verified that APNr activation ameliorated age-related muscle atrophy and excessive fat infiltration. APNr activation exerted dual effects on the regulation of myogenesis and adipogenesis of YMUSCs and AMUSCs and rescued age-related skeletal muscle dysfunction.

Puerarin improves skeletal muscle strength by regulating gut microbiota in young adult rats.

BackgroundSarcopenia is an age-related skeletal muscle dysfunction syndrome that is lacking validated treatments. Maximizing muscle strength in young adulthood may be a promising way to prevent sarcopenia in the elderly. The phytomolecule puerarin has been extensively used in clinical practice and reported to increase energy metabolism in skeletal muscle by directly targeting the skeletal muscle fiber. However, the bioavailability of puerarin is very poor, and almost 93% of puerarin stays in the intestine until excretion. Therefore, we hypothesize that puerarin may regulate gut microbiota to improve skeletal muscle strength and/or mass in adults.MethodsTwenty three-month old male Sprague Dawley rats were divided into two groups according to average weights, puerarin group (puerarin dissolved in 0.5% CMC-Na, 150 ​mg/kg/day, N ​= ​10), and control group (equal volume 0.5% CMC-Na, N ​= ​10). The treatment lasted for 8 weeks. Muscle weight, muscle fiber types and cross-sectional area (CSA), ex vivo muscle contraction test and grip strength were measured. 16S rDNA sequencing was employed to evaluate the gut microbiota composition in the sample of cecal content. Short-chain fatty acids (SCFAs) in cecal and serum were analyzed by gas chromatography-mass spectrometry. Adenosine triphosphate (ATP) concentration in skeletal muscle was also detected. Pearson's correlation was used to analyze the relations between SCFAs, ATP concentration and muscle function.ResultsAfter puerarin treatment, grip strength, the specific twitch force, and the tetanic forces in the soleus (SOL) and extensor digitorum longus (EDL) muscle were significantly higher than those of the control group. The percentage and CSA of type II muscle fiber in EDL was higher in the puerarin group than those in the control group. Puerarin treatment significantly changed the gut microbial constitutes. Two SCFAs-productive microbiota, the families Peptococcaceae and Closteridiales, were significantly higher in the puerarin group than those in the control group, while the ratio of Prevotellaceae/Bacteroidaceae (P/B), a muscle atrophy indicator, was lower in the puerarin group. As expected, there were significant linear correlations between the concentrations of SCFAs, including cecal total SCFAs, serum n-butyric acid and total SCFAs, and skeletal muscle strength and function, including the twitch force and tetanic force of SOL and EDL, as well as the forelimb grip strength.ConclusionIn conclusion, puerarin improved the forelimb grip strength and muscle contraction function in young adult rats. The underlying mechanism may include that puerarin increased SCFAs production by regulating gut microbiota, augmented ATP synthesis and skeletal muscle strength.The translational potential of this article: Our study finds that a clinical used phytomolecule puerarin has the potential of improving skeletal muscle strength in young adult rats. As puerarin has long-term clinical experience and shows good safety, it might be a potential candidate for developing muscle strengthening agents.

Lactobacillus paracasei PS23 dietary supplementation alleviates muscle aging via ghrelin stimulation in d-galactose-induced aging mice

• Lactobacillus paracasei PS23 (PS23) alleviates skeletal muscle atrophy in aging mice. • PS23 restores ghrelin levels in d -galactose-induced aging mice. • Ghrelin secretion in gastric cells is directly induced by PS23. • PS23 is a potential anti-aging dietary supplement that delays muscle aging. Some probiotics have been shown to alleviate age-related muscle atrophy via the gut-muscle axis. The aim of this study was to investigate the effects of live or heat-killed Lactobacillus paracasei PS23 (PS23) on muscle health in D-galactose-induced aging mice. Administration of D-galactose significantly reduced the strength, size, and levels of phosphorylated Akt in the muscle of mice. These effects were ameliorated by both live and heat-killed PS23 supplementation. Ghrelin is a multifaceted gut hormone with the ability to improve muscle atrophy. The levels of ghrelin in the serum and stomach of the aging mice were also significantly reduced and could be rescued by heat-killed but not live PS23. Furthermore, heat-killed PS23 greatly stimulated ghrelin secretion in the KATO III human gastric cell line. In conclusion, PS23 is a potential dietary supplement that can alleviate age-related muscle loss and dysfunction by regulating ghrelin secretion.

Metabolipidomic profiling reveals an age-related deficiency of skeletal muscle pro-resolving mediators that contributes to maladaptive tissue remodeling.

Specialized pro‐resolving mediators actively limit inflammation and support tissue regeneration, but their role in age‐related muscle dysfunction has not been explored. We profiled the mediator lipidome of aging muscle via liquid chromatography‐tandem mass spectrometry and tested whether treatment with the pro‐resolving mediator resolvin D1 (RvD1) could rejuvenate the regenerative ability of aged muscle. Aged mice displayed chronic muscle inflammation and this was associated with a basal deficiency of pro‐resolving mediators 8‐oxo‐RvD1, resolvin E3, and maresin 1, as well as many anti‐inflammatory cytochrome P450‐derived lipid epoxides. Following muscle injury, young and aged mice produced similar amounts of most pro‐inflammatory eicosanoid metabolites of cyclooxygenase (e.g., prostaglandin E2) and 12‐lipoxygenase (e.g., 12‐hydroxy‐eicosatetraenoic acid), but aged mice produced fewer markers of pro‐resolving mediators including the lipoxins (15‐hydroxy‐eicosatetraenoic acid), D‐resolvins/protectins (17‐hydroxy‐docosahexaenoic acid), E‐resolvins (18‐hydroxy‐eicosapentaenoic acid), and maresins (14‐hydroxy‐docosahexaenoic acid). Similar absences of downstream pro‐resolving mediators including lipoxin A4, resolvin D6, protectin D1/DX, and maresin 1 in aged muscle were associated with greater inflammation, impaired myofiber regeneration, and delayed recovery of strength. Daily intraperitoneal injection of RvD1 had minimal impact on intramuscular leukocyte infiltration and myofiber regeneration but suppressed inflammatory cytokine expression, limited fibrosis, and improved recovery of muscle function. We conclude that aging results in deficient local biosynthesis of specialized pro‐resolving mediators in muscle and that immunoresolvents may be attractive novel therapeutics for the treatment of muscular injuries and associated pain in the elderly, due to positive effects on recovery of muscle function without the negative side effects on tissue regeneration of non‐steroidal anti‐inflammatory drugs.

Profiling age-related muscle weakness and wasting: neuromuscular junction transmission as a driver of age-related physical decline.

Pathological age-related loss of skeletal muscle strength and mass contribute to impaired physical function in older adults. Factors that promote the development of these conditions remain incompletely understood, impeding development of effective and specific diagnostic and therapeutic approaches. Inconclusive evidence across species suggests disruption of action potential signal transmission at the neuromuscular junction (NMJ), the crucial connection between the nervous and muscular systems, as a possible contributor to age-related muscle dysfunction. Here we investigated age-related loss of NMJ function using clinically relevant, electrophysiological measures (single-fiber electromyography (SFEMG) and repetitive nerve stimulation (RNS)) in aged (26 months) versus young (6 months) F344 rats. Measures of muscle function (e.g., grip strength, peak plantarflexion contractility torque) and mass were assessed for correlations with physiological measures (e.g., indices of NMJ transmission). Other outcomes also included plantarflexion muscle contractility tetanic torque fade during 1-s trains of stimulation as well as gastrocnemius motor unit size and number. Profiling NMJ function in aged rats identified significant declines in NMJ transmission stability and reliability. Further, NMJ deficits were tightly correlated with hindlimb grip strength, gastrocnemius muscle weight, loss of peak contractility torque, degree of tetanic fade, and motor unit loss. Thus, these findings provide direct evidence for NMJ dysfunction as a potential mechanism of age-related muscle dysfunction pathogenesis and severity. These findings also suggest that NMJ transmission modulation may serve as a target for therapeutic development for age-related loss of physical function.

Chrono-Nutrition Has Potential in Preventing Age-Related Muscle Loss and Dysfunction.

The mammalian circadian clock systems regulate the day–night variation of several physiological functions such as the sleep/wake cycle and core body temperature. Disturbance in the circadian clock due to shiftwork and chronic jetlag is related to the risk of several disorders such as metabolic syndrome and cancer. Recently, it has been thought that shiftwork increases the risk of sarcopenia which is characterized by age-related decline of muscle mass and its dysfunctions including muscle strength and/or physical performance. First, we summarize the association between circadian rhythm and the occurrence of sarcopenia and discuss its mechanistic insight by focusing on the muscle function and molecular clock gene in knockout or mutant mice. The clock gene knockout or mutant mice showed early aging phenotypes, including low survival rate and muscle loss. It suggests that improvement in the disturbance of the circadian clock plays an important role in the aging process of healthy muscles. Nutritional intake has the potential to augment muscle growth and entrain the peripheral clock. Second, we discuss the potential of chrono-nutrition in preventing aging-related muscle loss and dysfunction. We also focus on the effects of time-restricted feeding (TRF) and the distribution of protein intake across three meals.

Quantifying the Effects of Aging on Morphological and Cellular Properties of Human Female Pelvic Floor Muscles.

Age-related pelvic floor muscle (PFM) dysfunction is a critical defect in the progression to pelvic floor disorders (PFDs). Despite dramatic prevalence of PFDs in older women, the underlying pathophysiology of age-related PFM dysfunction remains poorly understood. Using cadaveric specimens, we quantified aging effects on functionally relevant PFM properties and compared PFMs with the appendicular muscles from the same donors. PFMs, obturator internus, and vastus lateralis were procured from younger (N = 4) and older (N = 11) donors with known obstetrical and medical history. Our findings demonstrate that PFMs undergo degenerative, rather than atrophic, alterations. Importantly, age-related fibrotic degeneration disproportionally impacts PFMs compared to the appendicular muscles. We identified intramuscular lipid accumulation as another contributing factor to the pathological alterations of PFMs with aging. We observed a fourfold decrease in muscle stem cell (MuSC) pool of aged relative to younger PFMs, but the MuSC pool of appendicular muscles from the same older donors was only twofold lower than in younger group, although these differences were not statistically significant. Age-related degeneration appears to disproportionally impact PFMs relative to the appendicular muscles from the same donors. Knowledge of tissue- and cell-level changes in aged PFMs is essential to promote our understanding of the mechanisms governing PFM dysfunction in older women.

Age-Related Skeletal Muscle Dysfunction Is Aggravated by Obesity: An Investigation of Contractile Function, Implications and Treatment.

Obesity is a global epidemic and coupled with the unprecedented growth of the world’s older adult population, a growing number of individuals are both old and obese. Whilst both ageing and obesity are associated with an increased prevalence of chronic health conditions and a substantial economic burden, evidence suggests that the coincident effects exacerbate negative health outcomes. A significant contributor to such detrimental effects may be the reduction in the contractile performance of skeletal muscle, given that poor muscle function is related to chronic disease, poor quality of life and all-cause mortality. Whilst the effects of ageing and obesity independently on skeletal muscle function have been investigated, the combined effects are yet to be thoroughly explored. Given the importance of skeletal muscle to whole-body health and physical function, the present study sought to provide a review of the literature to: (1) summarise the effect of obesity on the age-induced reduction in skeletal muscle contractile function; (2) understand whether obesity effects on skeletal muscle are similar in young and old muscle; (3) consider the consequences of these changes to whole-body functional performance; (4) outline important future work along with the potential for targeted intervention strategies to mitigate potential detrimental effects.

Restoration of Sarcoplasmic Reticulum Ca2+ ATPase (SERCA) Activity Prevents Age-Related Muscle Atrophy and Weakness in Mice.

Sarcopenia has a significant negative impact on healthspan in the elderly and effective pharmacologic interventions remain elusive. We have previously demonstrated that sarcopenia is associated with reduced activity of the sarcoplasmic reticulum Ca2+ ATPase (SERCA) pump. We asked whether restoring SERCA activity using pharmacologic activation in aging mice could mitigate the sarcopenia phenotype. We treated 16-month male C57BL/6J mice with vehicle or CDN1163, an allosteric SERCA activator, for 10 months. At 26 months, maximal SERCA activity was reduced 41% in gastrocnemius muscle in vehicle-treated mice but maintained in old CDN1163 treated mice. Reductions in gastrocnemius mass (9%) and in vitro specific force generation in extensor digitorum longus muscle (11%) in 26 versus 16-month-old wild-type mice were also reversed by CDN1163. CDN1163 administered by intra-peritoneal injection also prevented the increase in mitochondrial ROS production in gastrocnemius muscles of aged mice. Transcriptomic analysis revealed that these effects are at least in part mediated by enhanced cellular energetics by activation of PGC1-α, UCP1, HSF1, and APMK and increased regenerative capacity by suppression of MEF2C and p38 MAPK signaling. Together, these exciting findings are the first to support that pharmacological targeting of SERCA can be an effective therapy to counter age-related muscle dysfunction.

Lower-limb muscle strength: normative data from an observational population-based study

BackgroundThe extent of muscle deterioration associated with ageing or disease can be quantified by comparison with appropriate reference data. The objective of this study is to present normative data for lower-limb muscle strength and quality for 573 males and 923 females aged 20-97 yr participating in the Geelong Osteoporosis Study in southeastern Australia.MethodsIn this cross-sectional study, measures of muscle strength for hip flexors and hip abductors were obtained using a Nicholas manual muscle tester, a hand-held dynamometer (HHD; kg). Leg lean mass was measured by dual energy x-ray absorptiometry (DXA; kg), and muscle quality calculated as strength/mass (N/kg).ResultsFor both sexes, muscle strength and quality decreased with advancing age. Age explained 12.9–25.3% of the variance in muscle strength in males, and 20.8–24.6% in females; age explained less of the variance in muscle quality. Means and standard deviations for muscle strength and quality for each muscle group are reported by age-decade for each sex, and cutpoints equivalent to T-scores of − 2.0 and − 1.0 were derived using data from young males (n = 89) and females (n = 148) aged 20–39 years.ConclusionsThese data will be useful for quantifying the extent of dynapenia and poor muscle quality among adults in the general population in the face of frailty, sarcopenia and other age-related muscle dysfunction.

GDF11 Implications in Cancer Biology and Metabolism. Facts and Controversies.

Growth Differentiation Factor 11 (GDF11), a member of the super family of the Transforming Growth Factor β, has gained more attention in the last few years due to numerous reports regarding its functions in other systems, which are different to those related to differentiation and embryonic development, such as age-related muscle dysfunction, skin biology, metabolism, and cancer. GDF11 is expressed in many tissues, including skeletal muscle, pancreas, kidney, nervous system, and retina, among others. GDF11 circulating levels and protein content in tissues are quite variable and are affected by pathological conditions or age. Although, GDF11 biology had a lot of controversies, must of them are only misunderstandings regarding the variability of its responses, which are independent of the tissue, grade of cellular differentiation or pathologies. A blunt fact regarding GDF11 biology is that its target cells have stemness feature, a property that could be found in certain adult cells in health and in disease, such as cancer cells. This review is focused to present and analyze the recent findings in the emerging research field of GDF11 function in cancer and metabolism, and discusses the controversies surrounding the biology of this atypical growth factor.