Age-related Muscle Atrophy Research Articles

Lactococcus cremoris subsp. cremoris FC-fermented milk activates protein synthesis and increases skeletal muscle mass in middle-aged mice

Age-related muscle atrophy is associated with decreased protein anabolic capacity. Dietary intervention is an important strategy for the treatment of age-related muscle atrophy. This study examined the effect of Lactococcus cremoris subsp. cremoris FC-fermented milk on muscle mass and protein anabolic signaling in middle-aged mice. Male C57BL/6J mice (18-month-old) were divided into the control and Lactococcus cremoris subsp. cremoris FC-fermented milk supplementation groups. Mice were administered unfermented or fermented milk (300 μL/day) by gavage every alternate day for 8 weeks; thereafter, muscle weight, protein metabolic signaling factors, and inflammatory factors were investigated. Soleus muscle weight was higher in the fermented milk group than in the control group. Expression of insulin growth factor-1, a typical anabolic factor, and phosphorylation levels of anabolic signaling factors (mTOR and p70S6K) were higher after fermented milk supplementation. Levels of tumor necrosis factor-α, an inhibitor of protein anabolism, were lower in the fermented milk group. These data suggest that the daily intake of Lactococcus cremoris subsp. cremoris FC-fermented milk increased skeletal muscle mass as well as protein synthesis in the middle-aged mice, which may be mediated by reduction in the levels of inflammatory factors. Therefore, accelerated protein synthesis, induced by the consumption of fermented milk, has a potential role in counteracting muscle atrophy.

Role of autophagy in the maintenance of skeletal muscle mass

As an important exercise and energy metabolism organ of the human body, the normal maintenance of skeletal muscle mass is essential for the body to perform normal physiological functions. The autophagy-lysosome (AL) pathway is a physiological or pathological mechanism that is ubiquitous in normal and diseased cells. It plays a key role in the maintaining of protein balance, removing damaged organelles, and the stability of internal environment. The smooth progress of the autophagy process needs to go through multiple steps, which are completed under the coordinated action of multiple factors. Autophagy maintains the muscle homeostasis of a healthy body by removing cell components such as damaged myofibrils and isolated cytoplasmic proteins. Autophagy could also provide the initial energy required for cell proliferation, promote muscle regeneration and remodeling after injury. At the same time, autophagy disorder is also an important cause of age-related skeletal muscle atrophy. Autophagy could affect the response of skeletal muscle to exercise, and increasing the level of basic autophagy is beneficial to improve the adaptive response of skeletal muscle to exercise. This article summarizes the role and pathways of autophagy in the maintenance of skeletal muscle quality, in order to provide effective rehabilitation strategies for clinical prevention and treatment of muscle atrophy.

Aldehyde dehydrogenase 2 deficiency promotes skeletal muscle atrophy in aged mice.

Aldehyde dehydrogenase 2 (ALDH2) detoxifies acetaldehyde produced from ethanol. A missense single nucleotide polymorphism (SNP) rs671 in ALDH2 exhibits a dominant-negative form of the ALDH2 protein. Nearly 40% of people in East Asia carry an inactive ALDH2*2 mutation. Previous studies reported that ALDH2*2 is associated with increased risk of several diseases. In this study, we examined the effect of ALDH2 deficiency on age-related muscle atrophy and its underlying mechanisms. We found that ALDH2 deficiency promotes age-related loss of muscle fiber cross-sectional areas, especially in oxidative fibers. Furthermore, ALDH2 deficiency exacerbated age-related accumulation of 4-hydroxy-2-nonenal (4-HNE), a marker of oxidative stress in the gastrocnemius muscle. Similarly, mitochondrial reactive oxygen species (ROS) production increased in aged ALDH2-knockout mice, indicating that ALDH2 deficiency induced mitochondrial dysfunction. In summary, ALDH2 deficiency promotes age-related muscle loss, especially in oxidative fibers, which may be associated with an increased accumulation of oxidative stress via mitochondrial dysfunction.

Lemon Myrtle (Backhousia citriodora) Extract and Its Active Compound, Casuarinin, Activate Skeletal Muscle Satellite Cells In Vitro and In Vivo.

Sarcopenia is an age-related skeletal muscle atrophy. Exercise is effective in improving sarcopenia via two mechanisms: activation of skeletal muscle satellite cells (SCs) and stimulation of muscle protein synthesis. In contrast, most nutritional approaches for improving sarcopenia focus mainly on muscle protein synthesis, and little is known about SC activation. Here, we investigated the effect of lemon myrtle extract (LM) on SC activation both in vitro and in vivo. Primary SCs or myoblast cell lines were treated with LM or its derived compounds, and incorporation of 5-bromo-2′-deoxyuridine, an indicator of cell cycle progression, was detected by immunocytochemistry. We found that LM significantly activated SCs (p < 0.05), but not myoblasts. We also identified casuarinin, an ellagitannin, as the active compound in LM involved in SC activation. The structure–activity relationship analysis showed that rather than the structure of each functional group of casuarinin, its overall structure is crucial for SC activation. Furthermore, SC activation by LM and casuarinin was associated with upregulation of interleukin-6 mRNA expression, which is essential for SC activation and proliferation. Finally, oral administration of LM or casuarinin to rats showed significant activation of SCs in skeletal muscle (p < 0.05), suggesting that LM and casuarinin may serve as novel nutritional interventions for improving sarcopenia through activating SCs.

Scavenging mitochondrial hydrogen peroxide by peroxiredoxin 3 overexpression attenuates contractile dysfunction and muscle atrophy in a murine model of accelerated sarcopenia.

Age‐related muscle atrophy and weakness, or sarcopenia, are significant contributors to compromised health and quality of life in the elderly. While the mechanisms driving this pathology are not fully defined, reactive oxygen species, neuromuscular junction (NMJ) disruption, and loss of innervation are important risk factors. The goal of this study is to determine the impact of mitochondrial hydrogen peroxide on neurogenic atrophy and contractile dysfunction. Mice with muscle‐specific overexpression of the mitochondrial H2O2 scavenger peroxiredoxin3 (mPRDX3) were crossed to Sod1KO mice, an established mouse model of sarcopenia, to determine whether reduced mitochondrial H2O2 can prevent or delay the redox‐dependent sarcopenia. Basal rates of H2O2 generation were elevated in isolated muscle mitochondria from Sod1KO, but normalized by mPRDX3 overexpression. The mPRDX3 overexpression prevented the declines in maximum mitochondrial oxygen consumption rate and calcium retention capacity in Sod1KO. Muscle atrophy in Sod1KO was mitigated by ~20% by mPRDX3 overexpression, which was associated with an increase in myofiber cross‐sectional area. With direct muscle stimulation, maximum isometric specific force was reduced by ~20% in Sod1KO mice, and mPRDX3 overexpression preserved specific force at wild‐type levels. The force deficit with nerve stimulation was exacerbated in Sod1KO compared to direct muscle stimulation, suggesting NMJ disruption in Sod1KO. Notably, this defect was not resolved by overexpression of mPRDX3. Our findings demonstrate that muscle‐specific PRDX3 overexpression reduces mitochondrial H2O2 generation, improves mitochondrial function, and mitigates loss of muscle quantity and quality, despite persisting NMJ impairment in a murine model of redox‐dependent sarcopenia.

Long Non-coding RNA MALAT1 Is Depleted With Age in Skeletal Muscle in vivo and MALAT1 Silencing Increases Expression of TGF-β1 in vitro

Long non-coding RNAs (lncRNAs) are thought to function as “sponges” for microRNAs, but a role for such competing endogenous RNAs (ceRNAs) in muscle aging is not well understood. We therefore examined in skeletal muscles of young (4–6 months) and aged (22–24) male and female mice the expression of lncRNA MALAT1, which is predicted in silico to bind the senescence-associated microRNA miR-34a-5p. Results indicate a significant decrease in lncRNA MALAT1 expression in mouse skeletal muscle with age that coincides with an age-related increase in miR-34a-5p expression. In vitro studies using mouse C2C12 myoblasts demonstrate that MALAT1 silencing using siRNA increases miR-34a expression, consistent with a role for MALAT1 as an inhibitor of miR-34a-5p activity. Levels of reactive oxygen species (ROS) are known to increase in muscle with age, and so we treated C2C12 cells with hydrogen peroxide (10 and 100 μM) to examine changes in MALAT1 expression. MALAT1 expression decreased significantly with H2O2 treatment, but this effect was attenuated with p53 siRNA. Finally, miR-34a-5p is implicated in tissue fibrosis, and so we assessed the expression of TGF-β1 after MALAT1 silencing. MALAT1 siRNA significantly increased the expression of TGF-β1 in C2C12 cells. These findings suggest that age-related fibrosis and muscle atrophy mediated by ROS may result at least in part from an increase in miR-34a bioavailability resulting from a decline in miR-34a “sponging” due to ceRNA MALAT1 depletion. Crosstalk between MALAT1 and miR-34a may therefore represent a therapeutic target for improving muscle function with aging.

Resveratrol attenuates age-related muscle atrophy and motor dysfunction by promoting autophagy in mice

Resveratrol attenuates age-related muscle atrophy and motor dysfunction by promoting autophagy in mice

Inhibitory Effects of Chrysanthemum (Chrysanthemum morifolium Ramat.) Extract and Its Active Compound Isochlorogenic Acid A on Sarcopenia.

Sarcopenia, age-related muscle atrophy, weakening muscle strength, and exercise capacity, generally accompany imbalances in protein metabolism. Chrysanthemum morifolium Ramat. extract (CME) and its active compound, isochlo-rogenic acid A (IcA), have been reported to have anti-oxidative, anti-diabetic, and neuroprotective effects. However, the roles of CME and IcA in the regulation of muscle protein turnover-related signaling pathways to attenuate sarcopenia have not been explored. In this study, we investigated CME and IcA based regulation of protein turnover in synthesizing muscle in vitro and in vivo. At the molecular level, CME and IcA promoted phosphorylation of PI3K/Akt and mTOR pathways, which stimulate synthesis of muscle proteins, and suppressed FoxO3a and E3 ubiquitin ligases during protein degrada-tion. In vivo, CME and IcA increased grip strength, exercise capacity, muscle mass and volume, and cross-sectional area of myofibers in middle-aged C57BL/6J mice. These results suggest that CME and IcA may have roles as functional food supplements for delaying sarcopenia by enhancing muscle mass recovery and function.

Depletion of the miR-34a “sponge” MALAT1 in aging skeletal muscle: Implications for age-related muscle loss

Abstract We have recently shown that increased levels of reactive oxygen species (ROS) in aging skeletal muscle are associated with increased expression of the senescence-associated microRNA miR-34a-5p (miR-34a). The histone deacetylase Sirt1 is a validated target of miR-34a, and miR-34a expression is induced by the tumor suppressor p53 which is itself stimulated by ROS. Long noncoding RNAs (lncRNAs) are known to function as “sponges” for microRNAs, but the role of such competing endogenous RNAs (ceRNA) in muscle aging is not well understood. We therefore examined in skeletal muscles of young (4-6 mos) and aged (22-24) male and female mice the expression of several lncRNAs that are predicted to bind miR-34a-5p in silico and whose predicted binding has been validated experimentally. Results indicate a significant decrease in lncRNA MALAT1 expression with aging. MALAT1 is known to be highly expressed during the later stages of myoblast differentiation and myotube maturation. We therefore treated C2C12 cells at 48 hrs with hydrogen peroxide (10 uM) and examined changes in MALAT1 expression. MALAT1 was significantly decreased with H2O2 treatment, whereas miR-34a is increased in C2C12 cells after hydrogen peroxide exposure. Age-related muscle atrophy mediated by ROS may therefore result in part from related mechanisms involving miR-34a activity: an increase in miR-34a targeting Sirt1 resulting from p53 activation and an increase in miR-34a bioavailability resulting from a decline in miR-34a “sponging” due to ceRNA MALAT1 depletion. These findings suggest that therapeutic interventions increasing MALAT1 expression in muscle may potentially enhance the preservation of muscle mass with aging.

Depletion of the miR-34a “sponge” MALAT1 in aging skeletal muscle: Implications for age-related muscle loss

We have recently shown that increased levels of reactive oxygen species (ROS) in aging skeletal muscle are associated with increased expression of the senescence-associated microRNA miR-34a-5p (miR-34a). The histone deacetylase Sirt1 is a validated target of miR-34a, and miR-34a expression is induced by the tumor suppressor p53 which is itself stimulated by ROS. Long noncoding RNAs (lncRNAs) are known to function as “sponges” for microRNAs, but the role of such competing endogenous RNAs (ceRNA) in muscle aging is not well understood. We therefore examined in skeletal muscles of young (4-6 mos) and aged (22-24) male and female mice the expression of several lncRNAs that are predicted to bind miR-34a-5p in silico and whose predicted binding has been validated experimentally. Results indicate a significant decrease in lncRNA MALAT1 expression with aging. MALAT1 is known to be highly expressed during the later stages of myoblast differentiation and myotube maturation. We therefore treated C2C12 cells at 48 hrs with hydrogen peroxide (10 uM) and examined changes in MALAT1 expression. MALAT1 was significantly decreased with H2O2 treatment, whereas miR-34a is increased in C2C12 cells after hydrogen peroxide exposure. Age-related muscle atrophy mediated by ROS may therefore result in part from related mechanisms involving miR-34a activity: an increase in miR-34a targeting Sirt1 resulting from p53 activation and an increase in miR-34a bioavailability resulting from a decline in miR-34a “sponging” due to ceRNA MALAT1 depletion. These findings suggest that therapeutic interventions increasing MALAT1 expression in muscle may potentially enhance the preservation of muscle mass with aging.

Aging Does Not Exacerbate Muscle Loss During Denervation and Lends Unique Muscle-Specific Atrophy Resistance With Akt Activation.

Sarcopenia, or age-related skeletal muscle atrophy and weakness, imposes significant clinical and economic burdens on affected patients and societies. Neurological degeneration, such as motoneuron death, has been recognized as a key contributor to sarcopenia. However, little is known about how aged/sarcopenic muscle adapts to this denervation stress. Here, we show that mice at 27months of age exhibit clear signs of sarcopenia but no accelerated denervation-induced muscle atrophy when compared to 8-month-old mice. Surprisingly, aging lends unique atrophy resistance to tibialis anteria muscle, accompanied by an increase in the cascade of mammalian target of rapamycin complex 1 (mTORC1)-independent anabolic events involving Akt signaling, rRNA biogenesis, and protein synthesis during denervation. These results expand our understanding of age-dependent stress responses and may help develop better countermeasures to sarcopenia.

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.

Prolonged caloric restriction ameliorates age-related atrophy in slow and fast muscle fibers of rat soleus muscle

Aging causes loss of skeletal muscle mass and function, which is called sarcopenia. While sarcopenia impairs the quality of life of older adults and is a major factor in long-term hospitalization, its detailed pathogenic mechanism and preventive measures remain to be identified. Caloric restriction (CR) suppresses age-related physiological and pathological changes in many species and prolongs the average and healthy life expectancy. It has recently been reported that CR suppresses the onset of sarcopenia; however, few studies have analyzed the effects of long-term CR on age-related skeletal muscle atrophy. Thus, we investigated the aging and CR effects on soleus (SOL) muscles of 9-, 24-, and 29-month-old ad libitum-fed rats (9AL, 24AL, and 29AL, respectively) and of 29-month-old CR (29CR) rats. The total muscle cross sectional area (mCSA) of the entire SOL muscle significantly decreased in the 29AL rats, but not in the 24AL rats, compared with the 9AL rats. SOL muscle of the 29AL rats exhibited marked muscle fiber atrophy and increases in the number of muscle fibers with a central nucleus, in fibrosis, and in adipocyte infiltration. Additionally, although the decrease in the single muscle fiber cross-sectional area (fCSA) and the muscle fibers' number occurred in both slow-type and fast-type muscle fibers, the degree of atrophy was more remarkable in the fast-type fibers. However, CR suppressed the muscle fiber atrophy observed in the 29AL rats' SOL muscle by preserving the mCSA and the number of muscle fibers that declined with aging, and by decreasing the number of muscle fibers with a central nucleus, fibrosis and denervated muscle fibers. Overall, these results revealed that advanced aging separately reduces the number and fCSA of each muscle fiber type, but long-term CR can ameliorate this age-related sarcopenic muscle atrophy.

Functional roles of non-coding RNAs in atrophy

Atrophy is defined as a reduction in cell, organ, or tissue size after reaching their normal mature sizes because of loss of organelles, cytoplasmic compartments, and proteins. This process is also involved in the pathogenesis of human disorders. Inadequate nourishment, poor circulation, inadequate hormonal support, defects in nerve supply of the tissue, disproportionate induction of apoptosis in the tissue, and absence of exercise are some underlying causes of atrophy. Recently, several non-coding RNAs (ncRNAs) have been identified that regulate atrophy, thus participating in the pathobiology of related disorders such as neurodegenerative/ neuromuscular diseases, age-related muscle atrophy, and cardiac tissue atrophy. In the current review, we have focused on two classes of ncRNAs namely long ncRNAs (lncRNAs) and microRNAs (miRNAs) to unravel their participation in atrophy-associated disorders.

Modulation of Ki67 and myogenic regulatory factor expression by tocotrienol-rich fraction ameliorates myogenic program of senescent human myoblasts.

IntroductionReplicative senescence results in dysregulation of cell proliferation and differentiation, which plays a role in the regenerative defects observed during age-related muscle atrophy. Vitamin E is a well-known antioxidant, which potentially ameliorates a wide range of age-related manifestations. The aim of this study was to determine the effects of tocotrienol-rich fraction (TRF) in modulating the expression of proliferation- and differentiation-associated proteins in senescent human myoblasts during the differentiation phase.Material and methodsHuman skeletal muscle myoblasts were cultured until senescence. Young and senescent cells were treated with TRF for 24 h before and after differentiation induction, followed by evaluation of cellular morphology and efficiency of differentiation. Expression of cell proliferation marker Ki67 protein and myogenic regulatory factors MyoD and myogenin were determined.ResultsOur findings showed that treatment with TRF significantly improved the morphology of senescent myoblasts. Promotion of differentiation was observed in young and senescent myoblasts with TRF treatment as shown by the increased fusion index and larger size of myotubes. Increased Ki67 and myogenin expression with TRF treatment was also observed in senescent myoblasts, suggesting amelioration of the myogenic program by TRF during replicative senescence.ConclusionsTRF modulates the expression of regulatory factors related to proliferation and differentiation in senescent human myoblasts and could be beneficial for ameliorating the regenerative defects during aging.

A Review of the Role of Endo/Sarcoplasmic Reticulum-Mitochondria Ca2+ Transport in Diseases and Skeletal Muscle Function.

The physical contact site between a mitochondrion and endoplasmic reticulum (ER), named the mitochondria-associated membrane (MAM), has emerged as a fundamental platform for regulating the functions of the two organelles and several cellular processes. This includes Ca2+ transport from the ER to mitochondria, mitochondrial dynamics, autophagy, apoptosis signalling, ER stress signalling, redox reaction, and membrane structure maintenance. Consequently, the MAM is suggested to be involved in, and as a possible therapeutic target for, some common diseases and impairment in skeletal muscle function, such as insulin resistance and diabetes, obesity, neurodegenerative diseases, Duchenne muscular dystrophy, age-related muscle atrophy, and exercise-induced muscle damage. In the past decade, evidence suggests that alterations in Ca2+ transport from the ER to mitochondria, mediated by the macromolecular complex formed by IP3R, Grp75, and VDAC1, may be a universal mechanism for how ER-mitochondria cross-talk is involved in different physiological/pathological conditions mentioned above. A better understanding of the ER (or sarcoplasmic reticulum in muscle)-mitochondria Ca2+ transport system may provide a new perspective for exploring the mechanism of how the MAM is involved in the pathology of diseases and skeletal muscle dysfunction. This review provides a summary of recent research findings in this area.

Iron accumulation in skeletal muscles of old mice is associated with impaired regeneration after ischaemia-reperfusion damage.

BackgroundOxidative stress is implicated in the insidious loss of muscle mass and strength that occurs with age. However, few studies have investigated the role of iron, which is elevated during ageing, in age‐related muscle wasting and blunted repair after injury. We hypothesized that iron accumulation leads to membrane lipid peroxidation, muscle wasting, increased susceptibility to injury, and impaired muscle regeneration.MethodsTo examine the role of iron in age‐related muscle atrophy, we compared the skeletal muscles of 3‐month‐old with 22‐ to 24‐month‐old 129SvEv FVBM mice. We assessed iron distribution and total elemental iron using laser ablation inductively coupled plasma mass spectrometry and Perls' stain on skeletal muscle cross‐sections. In addition, old mice underwent ischaemia–reperfusion (IR) injury (90 min ischaemia), and muscle regeneration was assessed 14 days after injury. Immunoblotting was used to determine lipid peroxidation (4HNE) and iron‐related proteins. To determine whether muscle iron content can be altered, old mice were treated with deferiprone (DFP) in the drinking water, and we assessed its effects on muscle regeneration after injury.ResultsWe observed a significant increase in total elemental iron (+43%, P < 0.05) and lipid peroxidation (4HNE: +76%, P < 0.05) in tibialis anterior muscles of old mice. Iron was further increased after injury (adult: +81%, old: +135%, P < 0.05) and associated with increased lipid peroxidation (+41%, P < 0.05). Administration of DFP did not impact iron or measures of lipid peroxidation in skeletal muscle or modulate muscle mass. Increased muscle iron concentration and lipid peroxidation were associated with less efficient regeneration, evident from the smaller fibres in cross‐sections of tibialis anterior muscles (−24%, P < 0.05) and an increased percentage of fibres with centralized nuclei (+4124%, P < 0.05) in muscles of old compared with adult mice. Administration of DFP lowered iron after IR injury (PRE: −32%, P < 0.05 and POST: −41%, P < 0.05), but did not translate to structural improvements.ConclusionsMuscles from old mice have increased iron levels, which are associated with increased lipid peroxidation, increased susceptibility to IR injury, and impaired muscle regeneration. Our results suggest that iron is involved in effective muscle regeneration, highlighting the importance of iron homeostasis in muscle atrophy and muscle repair.

Maintenance of type 2 glycolytic myofibers with age by Mib1-Actn3 axis

Age-associated muscle atrophy is a debilitating condition associated with loss of muscle mass and function with age that contributes to limitation of mobility and locomotion. However, the underlying mechanisms of how intrinsic muscle changes with age are largely unknown. Here we report that, with age, Mind bomb-1 (Mib1) plays important role in skeletal muscle maintenance via proteasomal degradation-dependent regulation of α-actinin 3 (Actn3). The disruption of Mib1 in myofibers (Mib1ΔMF) results in alteration of type 2 glycolytic myofibers, muscle atrophy, impaired muscle function, and Actn3 accumulation. After chronic exercise, Mib1ΔMF mice show muscle atrophy even at young age. However, when Actn3 level is downregulated, chronic exercise-induced muscle atrophy is ameliorated. Importantly, the Mib1 and Actn3 levels show clinical relevance in human skeletal muscles accompanied by decrease in skeletal muscle function with age. Together, these findings reveal the significance of the Mib1-Actn3 axis in skeletal muscle maintenance with age and suggest the therapeutic potential for the treatment or amelioration of age-related muscle atrophy.

Unique Characteristics of Quadriceps Muscle Morphology and Function in Older Tennis Players.

We investigated the quadriceps muscle size and quantitative characteristics in older tennis players. Thirty-eight senior tennis players (70.8 ± 5.3years) and 38 controls (71.6 ± 5.1years) were included. To measure the muscle size and quality, we measured muscle thickness in the rectus femoris (RF), vastus lateralis, and vastus intermedius, and muscle echo intensity in the RF and vastus lateralis using B-mode transverse ultrasound, respectively. We measured knee extension peak torque for muscle function. Muscle thickness in the RF, vastus lateralis, and vastus intermedius were significantly larger in tennis players than in controls. Tennis players had a lower echo intensity in RF and a higher knee extension peak torque compared to controls. Stepwise multiple linear regression analysis implied that echo intensity and muscle thickness were predictors of knee extension peak torque. Higher muscle quality contributes to a higher knee extension peak torque in tennis players. Playing tennis may prevent age-related muscle atrophy and maintain muscle quality in older individuals.

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.