DPP4 inhibitors as a potential therapeutic option for sarcopenia: A 6-month follow-up study in diabetic older patients.

OBJECTIVES: Sarcopenia is associated with increased morbidity and mortality in older adults with type 2 diabetes mellitus (T2DM). This study investigates the effects of dipeptidyl peptidase-4 inhibitors (DPP4i) as an add-on therapy for sarcopenia in older adults with T2DM over a six-month follow-up period. METHODS: This is a retrospective and six-month follow-up study. The study was performed on 90 participants who are followed in a geriatric clinic hospital. Sarcopenia was diagnosed as per the EGWSOP-2 criteria. The patients were divided into two groups regarding DPP4i use. Each patient was evaluated for sarcopenia and sarcopenia-related parameters at baseline and at the end of 6 months. RESULTS: The mean age of the patients was 72.57 ± 7.089, and 60% of them were female. DPP4i users had worse glycemic control and decreased rate of low muscle strength at the end of 6 months (39.6% vs. 25.0%, P = .039). Forty-two patients without DPP4i therapy had reduced muscle strength (22.71 ± 6.95 kg vs. 20.88 ± 6.32 kg, P = .046) and stable Hba1c levels (6.45 ± 0.56% vs. 6.40 ± 0.52, P = .380) at their six-month follow-up control. CONCLUSIONS: Adding DPP4i to treatment for T2DM yields a positive effect on muscle strength and glycemic control. These agents may offer higher prospects in managing T2DM while counteracting sarcopenia. BRIEF SUMMARY: T2DM and Sarcopenia are common in older adults. Considering the increased prevalence of T2DM and the risk of coexistent sarcopenia in older adults, the additional positive effects of DPP4i may be crucial in the choice of treatment for these patients.

Passive repetitive stretching is associated with greater muscle mass and cross-sectional area in the sarcopenic muscle.

Mechanical stimulation has benefits for muscle mass and function. Passive stretching is widely performed in clinical rehabilitation medicine. However, the hypertrophic effects of passive repetitive stretching on senescent skeletal muscles against muscle atrophy remain unknown. We used senescence-accelerated model SAM-P8 mice. The gastrocnemius muscle was passively repetitive stretched by manual ankle dorsiflexion for 15 min, 5 days a week for 2 weeks under deep anesthesia. We examined the effects of passive stretching on muscle mass, myofiber cross-sectional area, muscle fiber type composition, satellite cell and myonuclei content, signaling pathways involved in muscle protein synthesis, and myogenic regulatory factors. The gastrocnemius muscle weight and fiber cross-sectional area of the stretched side was found greater compared with that of the unstretched side. Passive repetitive stretching increased the mRNA expression level of Akt, p70S6K, 4E-BP1, Myf5, myogenin, MuRF1.The phosphorylation level of p70S6K significantly increased in the stretched muscles, whereas of Akt and 4E-BP1 remained unchanged, compared to the unstretched side. The Pax7+ cells and myonuclei content did not differ between the stretched and unstretched muscles. These findings suggest that the hypertrophic or suppressed atrophic observation in the stretched muscles are mainly attributable to the protein turnover provoked by stretching. These findings are applicable to clinical muscle strengthening and sarcopenia prevention.

Muscle fiber type specific alterations of mitochondrial respiratory function and morphology in aged female mice.

Mitochondrial dysfunction is considered to be a major cause of sarcopenia, defined as age-related muscle fiber atrophy and muscle weakness, as reduced mitochondrial respiration and morphological changes such as ragged red fibers (RRFs) are observed in aging muscles. However, the role of mitochondrial dysfunction in sarcopenia is not fully elucidated. Although previous studies have suggested that aging has a fiber type-specific effect on mitochondrial function, little is known about mitochondrial changes in individual fiber types. Here, we used C57BL/6NCr female mice to identify fiber type-specific pathological changes, examine the significance of pathological changes in sarcopenia, and identify possible mechanisms behind mitochondrial changes in slow-twitch soleus muscle (SOL) and fast-twitch extensor digitorum longus muscle (EDL). We observed reduced type I fiber-specific mitochondrial respiratory enzyme activity, impaired respiration, and subsarcolemmal mitochondrial accumulation in aged SOL, which was different from RRFs. These pathological alterations were not directly associated with fiber atrophy. Additionally, we found increased oxidative stress markers in aged SOL, suggesting that oxidative stress is involved in the pathological and functional changes in mitochondria. Meanwhile, obvious mitochondrial changes were not seen in aged EDL. Thus, age-related mitochondrial dysfunction is specific to the fiber type and may correlate with the muscle quality rather than the muscle mass.

Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength.

Treatments are lacking for sarcopenia, a debilitating age-related skeletal muscle wasting syndrome. We identifed increased amounts of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the prostaglandin E2 (PGE2)-degrading enzyme, as a hallmark of aged tissues, including skeletal muscle. The consequent reduction in PGE2 signaling contributed to muscle atrophy in aged mice and results from 15-PGDH-expressing myofibers and interstitial cells, such as macrophages, within muscle. Overexpression of 15-PGDH in young muscles induced atrophy. Inhibition of 15-PGDH, by targeted genetic depletion or a small-molecule inhibitor, increased aged muscle mass, strength, and exercise performance. These benefits arise from a physiological increase in PGE2 concentrations, which augmented mitochondrial function and autophagy and decreased transforming growth factor-ß signaling and activity of ubiquitin-proteasome pathways. Thus, PGE2 signaling ameliorates muscle atrophy and rejuvenates muscle function, and 15-PGDH may be a suitable therapeutic target for countering sarcopenia.

Baseline low ALT activity is associated with increased long-term mortality after COPD exacerbations.

BACKGROUND: COPD exacerbations have negative impact on patients' survival. Several risk factors for grave outcomes of such exacerbations have been descried. Muscle dysfunction and mass loss were shown to impact negatively on prognosis and survival. Low activity of the enzyme ALT (Alanine amino-transferase) in the blood is a known indicator for sarcopenia and frailty, however, no previous studies addressed the association of low ALT amongst patients hospitalized due to COPD exacerbation and long-term survival. METHODS: This is a historic prospective cohort study of patients hospitalized due to acute COPD exacerbation. RESULTS: Included were 232 consecutive COPD exacerbation patients. The median time of follow-up was 34.9 months (IQR 23.13-41.73 months). During this period 104 (44.8%) patients died. All patients were grouped to quartiles according to blood ALT levels (after exclusion of cases considered to have hepatic tissue damage (ALT > 40 IU)). The risk of long-term mortality increased, in a statistically significant manner, amongst patients with low ALT values: the median survival of patients with ALT < 11 IU was 18.5 months only while the median survival for the rest of the study group was not reached. For ALT < 11 IU; 12-16 IU; 17-20 IU and > 21 IU the mortality rates were 69%; 40.9%; 36.3 and 25% respectively (p <  0.001 for comparison of lower quartile with upper three quartiles). The crude hazard ratio for mortality amongst patients with ALT levels lower than 11 IU was 2.37 (95% CI; 1.6-3.5). This increased risk of mortality remained significant after adjustment for age, weight, creatinine, albumin concentration and cardiovascular diseases (HR = 1.83; 95% CI 1.08-3.1, p <  0.05). CONCLUSIONS: Low ALT values, a biomarker of sarcopenia and frailty, are associated with poor long-term survival amongst patients hospitalized due to COPD exacerbation.

The autophagic-lysosomal and ubiquitin proteasome systems are simultaneously activated in the skeletal muscle of gastric cancer patients with cachexia.

BACKGROUND: Cancer cachexia is characterized by weight loss, especially ongoing skeletal muscle loss, and is associated with poor patient outcomes. However, the molecular mechanism of skeletal muscle wasting is not fully understood. OBJECTIVES: We aimed to investigate muscle fiber morphology and proteolysis system activity changes that may account for cancer cachexia and to relate these changes to patients' clinical phenotypes. METHODS: We divided 39 patients with resectable gastric cancer into 4 groups based on the presence of cachexia (weight loss) and/or sarcopenia (low muscularity), including a noncachexia/nonsarcopenia group (N, n = 10), a cachexia/sarcopenia group (CS, n = 13), a cachexia/nonsarcopenia group (C, n = 9), and a noncachexia/sarcopenia group (S, n = 7). Rectus abdominis muscle biopsy specimens were obtained intraoperatively. Muscle fiber size, ultrastructural architecture, and the expression of autophagic-lysosomal system (ALS) and ubiquitin proteasome system (UPS) markers were assayed. RESULTS: Mean ± SD muscle fiber cross-sectional areas were significantly decreased in the CS (460 ± 120 µm2) and S groups (480 ± 135 µm2) compared with the N (1615 ± 388 µm2, both P < 0.05) and C groups (1219 ± 302 µm2, both P < 0.05). In the C, S, and CS groups, the muscle exhibited tissue disorganization and autophagosome formation to different degrees. The levels of ALS and UPS markers were significantly increased in the CS, C, and S groups compared with the N group. Alterations in muscle fiber morphology and increased ALS and UPS activity were related to severe muscle loss, but not weight loss. CONCLUSIONS: The ALS and UPS are simultaneously activated in cancer cachexia and may play coordinated roles in cachexia-induced muscle loss.

Aging reduces succinate dehydrogenase activity in rat type IIx/IIb diaphragm muscle fibers.

In aged rats, diaphragm muscle (DIAm) reduced specific force and fiber cross-sectional area, sarcopenia, is selective for vulnerable type IIx and/or IIb DIAm fibers, with type I and IIa fibers being resilient. In humans, the oxidative capacity [as measured by maximum succinate dehydrogenase (SDHmax) activity] of fast-type muscle is reduced with aging, with slow-type muscle being unaffected. We hypothesized that in aged Fischer rat DIAm exhibiting sarcopenia, reduced SDHmax activity would occur in type IIx and/or IIb fibers. Rats obtained from the NIA colony (6, 18, and 24 mo old) were euthanized, and ~2-mm-wide DIAm strips were obtained. For SDHmax and fiber type assessments, DIAm strips were stretched (approximately optimal length), fresh frozen in isopentane, and sectioned on a cryostat at 6 µm. SDHmax, quantified by intensity of nitroblue tetrazolium diformazan precipitation, was assessed in a fiber type-specific manner by comparing serial sections labeled with myosin heavy chain (MyHC) antibodies differentiating type I (MyHCSlow), IIa (MyHC2A), and IIx and/or IIb fibers. Isometric DIAm force and fatigue were assessed in DIAm strips by muscle stimulation with supramaximal pulses at a variety of frequencies (5-100 Hz) delivered in 1-s trains. By 24 mo, DIAm sarcopenia was apparent and SDHmax in type IIx and/or IIb fibers activity was reduced ~35% compared with 6-mo-old control DIAm. These results underscore the remarkable fiber type selectivity of type IIx and/or IIb fibers to age-associated perturbations and suggest that reduced mitochondrial oxidative capacity is associated with DIAm sarcopenia.NEW & NOTEWORTHY We examined the oxidative capacity as measured by maximum succinate dehydrogenase activity in older (18 or 24 mo old) Fischer 344 rat diaphragm muscle (DIAm) compared with young rats (6 mo old). In 24-mo-old rats, SDH activity was reduced in type IIx/b DIAm fibers. These SDH changes were concomitant with sarcopenia (reduced specific force and atrophy of type IIx/b DIAm fibers) at 24 mo old. At 18 mo old, there was no change in SDH activity and no evidence of sarcopenia.

Matrix metalloprotease 3 is associated with sarcopenia in rheumatoid arthritis - results from the CHIKARA study.

AIM: Patients with rheumatoid arthritis (RA) show lower muscle mass and a higher prevalence of sarcopenia than healthy individuals. Correlations between sarcopenia and disease activity, physical function, laboratory data and body composition at baseline were investigated in a prospective, observational study (CHIKARA study) of RA patients. METHODS: Body composition was measured using a bioelectrical impedance analyzer. Parameters were compared between sarcopenia and non-sarcopenia groups, and correlations between sarcopenia and Disease Activity Score of 28 joints - erythrocyte sedimentation rate (DAS28-ESR), modified health assessment questionnaire, treatment, and laboratory data, including matrix metalloproteinase 3 (MMP3), were investigated. RESULTS: The participants were 100 patients with RA (women, 78%; mean age, 66.1 years). Mean disease duration was 5.5 years, DAS28-ESR was 3.55 and the prevalence of sarcopenia was 28%. Median C-reactive protein (CRP) and MMP3 were significantly higher in the sarcopenia group (0.21 mg/dL and 103.4 ng/mL) than in the non-sarcopenia group (0.11 mg/dL and 70.3 ng/mL). Sarcopenia was negatively correlated with weight, body mass index (BMI), muscle mass, body fat mass, estimated bone mass and basal metabolic rate, and positively correlated with Steinbrocker stage, CRP and MMP3 on univariate analyses. BMI, body fat mass and MMP3 were independently associated with sarcopenia on multivariate logistic regression analysis. When MMP3 was ≥ 90.7 ng/mL, the odds ratio for sarcopenia was increased 3.1-fold compared with < 90.7 ng/mL (P = 0.018). CONCLUSION: The prevalence of sarcopenia was 28% in patients with RA whose disease activity was mild. Low BMI, high fat mass and high MMP3 were independently associated with sarcopenia. MMP3 might be a useful marker for sarcopenia in patients with RA.

Deletion Polymorphism of Angiotensin-Converting Enzyme Gene Is Associated with Low Muscle Mass in Elderly People in Jakarta, Indonesia.

Decline in muscle mass due to aging is a growing public health problem as it contributes to a decreased capacity for independent living among elderly people. A clear understanding of genetic factors is important, as it is known that angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphism affects muscle mass, although the findings are frequently heterogeneous. This study was conducted to determine the association between ACE I/D polymorphism and muscle mass in elderly people. A total of 130 elderly people were recruited from nursing homes in Jakarta. Anthropometric components affecting the muscle mass were examined. Cross-sectional analyses were performed to compare data using t-test, ANOVA and ANCOVA, and linear regression. Genotyping of the ACE I/D polymorphisms was performed by PCR methods, and muscle mass was evaluated by BIA. Genotype distribution counts II 65.38%, ID 13.85%, and DD 20.77% were not consistent with the Hardy-Weinberg equilibrium (χ² = 22.2, df = 2; p < 0.01). Individuals with the DD genotype showed lower muscle mass that was significantly different compared to the muscle mass in individuals with the II/ID genotype (II 16.14 ± 0.38, ID 15.71 ± 0.59; DD 13.95 ± 0.61 kg), after adjusting for % fat as a covariate. The linear regression analysis showed that age, gender, weight, height, nutritional status, protein content, and waist, hip, and calf circumference were significant contributors to muscle mass. In the multivariate analysis, adjusted age and gender significantly correlated with muscle mass, with r² = 0.98, by the likelihood ratio test (p < 0.01). The genotype variability accounted for 2.65% of the DD genotype. This study showed that in an elderly population in Jakarta, the DD genotype was associated with low muscle mass. This result suggests the role of nutritional status as a potential mediator in the association between ACE gene and muscle mass.

Low Alanine Aminotransferase Levels in the Elderly Population: Frailty, Disability, Sarcopenia, and Reduced Survival.

Background: Although low alanine aminotransferase (ALT) levels have been associated with poor outcomes in the elderly population, the determinants subtending this association have been poorly explored. To gain insight into this topic, we analyzed data from a prospective population-based database (InCHIANTI study) in which frailty, disability, sarcopenia, and pyridoxine levels were systematically assessed. Methods: Data are from 765 participants aged more than 65 years (mean age 75.3 years, women 61.8%), without chronic liver disease, malignancies, or alcohol abuse. Frailty was defined according to Fried criteria, sarcopenia through peripheral Quantitative-Computed-Tomography (lowest gender-specific tertile of the residuals of a linear regression of muscle mass from height and fat mass), and disability as self-reported need for help in at least one basic daily living activity. Associations of ALT with overall and cardiovascular mortality were assessed by Cox-models with time-dependent covariates. Results: ALT activity was inversely associated with frailty, sarcopenia, disability, and pyridoxine deficiency; however, higher ALT was confirmed to be protective with respect of overall and cardiovascular mortality even in multiple-adjusted models including all these covariates (overall: hazard ratio [HR] 0.98 [0.96-1], p = .02; cardiovascular: 0.94 [0.9-0.98], p < .01). The association between ALT activity and mortality was nonlinear (J-shaped), and subjects in the lower quintiles of ALT levels showed a sharply increased overall and cardiovascular mortality. Conclusions: These results suggest that reduced ALT levels in older individuals can be considered as a marker of frailty, disability, and sarcopenia, and as an independent predictor of adverse outcomes. The possible relationship between reduced ALT and impaired hepatic metabolic functions should be explored.

Fermented Rice Germ Extract Alleviates Morphological and Functional Damage to Murine Gastrocnemius Muscle by Inactivation of AMP-Activated Protein Kinase.

Sarcopenia, loss of muscle mass and function, is mainly observed in elderly people. In this study, we investigated whether fermented rice germ extract (FRGE) has some effects on the mouse gastrocnemius muscle by using behavioral and morphological analyses, Western blotting, and a murine model of immobilization-induced muscle atrophy. Daily oral FRGE administration increased muscle weight and strength. In addition, myofiber size in gastrocnemius muscle of FRGE-treated mice was increased as revealed by morphological quantification. Activation of AMP-activated protein kinase (AMPK) signaling, which inhibits protein synthesis and stimulates protein degradation in gastrocnemius muscle, was significantly attenuated in the FRGE-treated mice compared with control mice. Expression level of forkhead box 3a (FOXO3a) protein was also significantly decreased in the FRGE-treated group. Moreover, the decrease in mean myofiber cross-sectional area in immobilized hindlimb in vehicle-treated mice was inhibited by FRGE treatment in histological analysis. In conclusion, FRGE increased the strength and weight of gastrocnemius muscle and myofiber size, and reduced immobilization-induced muscle atrophy in mice. These findings indicated that FRGE might be beneficial in preventing motor dysfunction in a range of conditions, including sarcopenia.

The effect of exercise, resveratrol or their combination on Sarcopenia in aged rats via regulation of AMPK/Sirt1 pathway.

Sarcopenia is an age-related syndrome characterized by progressive loss of muscle mass and function. Exercise is an important strategy to prolong life and increase muscle mass, and resveratrol has been shown a variety beneficial effects on skeletal muscle. In the present study, we investigated the potential efficacy of using short-term exercise (six weeks), resveratrol (150mg/kg/day), or combined exercise+resveratrol (150mg/kg/day) on gastrocnemius muscle mass, grip strength, cross-sectional area and microscopic morphology in aged rats, and explored the potential mechanism at the apoptosis level. Six months old SD rats were used as young control group and 24months old SD rats were adopted as aged group. After six weeks intervention, the data provide evidence that exercise, resveratrol or their combination significantly increase the relative grip strength and muscle mass in aged rats (P<0.05). Electron microscopy discovered a significant increase in sarcomere length, I-band and H-zone in aged rats (P<0.05), and exercise, resveratrol or their combination significantly reduced the increasement (P<0.05). Moreover, light microscopy revealed a significant increase on Feret's diameter and cross-sectional area (CSA) in aged rats (P<0.05), but exercise and resveratrol did not show significant effects on them (P>0.05). Furthermore, exercise, resveratrol or their combination significantly increased the expression of p-AMPK and SIRT1, decreased the expression of acetyl P53 and Bax/Bcl-2 ratio in aged rats (P<0.05). These findings show that aged rats show significant changes in gastrocnemius muscle morphology and ultrastructure, and the protective effects of exercise, resveratrol and their combination are probably associated with anti-apoptotic signaling pathways through activation of AMPK/Sirt1.

11ß-Hydroxysteroid dehydrogenase type 1 within muscle protects against the adverse effects of local inflammation.

Muscle wasting is a common feature of inflammatory myopathies. Glucocorticoids (GCs), although effective at suppressing inflammation and inflammatory muscle loss, also cause myopathy with prolonged administration. 11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is a bidirectional GC-activating enzyme that is potently upregulated by inflammation within mesenchymal-derived tissues. We assessed the regulation of this enzyme with inflammation in muscle, and examined its functional impact on muscle. The expression of 11ß-HSD1 in response to proinflammatory stimuli was determined in a transgenic murine model of chronic inflammation (TNF-Tg) driven by overexpression of tumour necrosis factor (TNF)-α within tissues, including muscle. The inflammatory regulation and functional consequences of 11ß-HSD1 expression were examined in primary cultures of human and murine myotubes and human and murine muscle biopsies ex vivo. The contributions of 11ß-HSD1 to muscle inflammation and wasting were assessed in vivo with the TNF-Tg mouse on an 11ß-HSD1 null background. 11ß-HSD1 was significantly upregulated within the tibialis anterior and quadriceps muscles from TNF-Tg mice. In human and murine primary myotubes, 11ß-HSD1 expression and activity were significantly increased in response to the proinflammatory cytokine TNF-α (mRNA, 7.6-fold, p < 0.005; activity, 4.1-fold, p < 0.005). Physiologically relevant levels of endogenous GCs activated by 11ß-HSD1 suppressed proinflammatory cytokine output (interkeukin-6, TNF-α, and interferon-γ), but had little impact on markers of muscle wasting in human myotube cultures. TNF-Tg mice on an 11ß-11ß-HSD1 knockout background developed greater muscle wasting than their TNF-Tg counterparts (27.4% less; p < 0.005), with smaller compacted muscle fibres and increased proinflammatory gene expression relative to TNF-Tg mice with normal 11ß-HSD1 activity. This study demonstrates that inflammatory stimuli upregulate 11ß-HSD1 expression and GC activation within muscle. Although concerns have been raised that excess levels of GCs may be detrimental to muscle, in this inflammatory TNF-α-driven model, local endogenous GC activation appears to be an important anti-inflammatory response that protects against inflammatory muscle wasting in vivo. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Response of BAX, Bcl-2 Proteins, and SIRT1/PGC-1α mRNA Expression to 8-Week Treadmill Running in the Aging Rat Skeletal Muscle.

The aim of this study was to analyze the effects of exercise training on Bax and Bcl-2 protein content and sirtuin1 (SIRT1) mRNA expression levels to prevent sarcopenia in aging rats. Eight 18 months old male Sprague-Dawley rats were trained 5 days weekly for 8 weeks on a treadmill, and eight sedentary rats served as controls. Gastrocnemius muscles were dissected 2 days after the last training session. The mRNA content of PGC-1α, caspase-3, NRF1, TFAM, SOD2, and SIRT1 was estimated by RT-PCR with GAPDH used as an internal control. The protein expression of BAX and Bcl-2 was assessed by Western immunoblot. After training, significant (p < 0.05) increases were noted for the gastrocnemius muscle weights, the gastrocnemius mass/body mass ratio, the bcl-2/BAX ratio, the Bcl-2 protein and the SIRT1, PGC-1α, NRF1, TFAM, SOD2 mRNA content in the trained gastrocnemius, relative to the control samples. No difference was found in the BAX protein between control and trained muscles, whereas the caspase-3 mRNA content decreased by 50 %, in the gastrocnemius muscle of trained animals. Exercise training may inhibit age-induced myonuclear apoptosis by stimulating SIRT1/PGC-1α mRNA expression, thereby preventing sarcopenia in aging rat.

Hyperhomocysteinemia inhibits satellite cell regenerative capacity through p38 alpha/beta MAPK signaling.

Chronic failure in maintenance and regeneration of skeletal muscles leads to lower muscle mass (sarcopenia), muscle weakness, and poor response to injury. Evidence suggests that aberrant p38 MAPK signaling undermines the repair process after injury in aged mice. Previous studies have shown that hyperhomocysteinemia (HHcy) has been associated with muscle weakness and lower than normal body weights. However, whether or not HHcy condition also compromises skeletal muscle regenerative capabilities is not clear. In the current study, we show that CBS-/+ mice, a model for HHcy condition, exhibited compromised regenerative function and cell proliferation upon injury. However, there was no significant difference in Pax7 expression levels in the satellite cells from CBS-/+ mouse skeletal muscles. Interestingly, the satellite cells from CBS-/+ mice not only exhibited diminished in vitro proliferative capabilities, but also there was heightened oxidative stress. In addition, there was enhanced p38 MAPK activation as well as p16 and p21 expression in the CBS-/+ mouse satellite cells. Moreover, the C2C12 myoblasts also exhibited higher p38 MAPK activation and p16 expression upon treatment with homocysteine in addition to enhanced ROS presence. Tissue engraftment potential and regeneration after injury were restored to some extent upon treatment with the p38-MAPK inhibitor, SB203580, in the CBS-/+ mice. These results together suggest that HHcy-induced diminished satellite cell proliferation involves excessive oxidative stress and p38 MAPK signaling. Our study further proposes that HHcy is a potential risk factor for elderly frailty, and need to be considered as a therapeutic target while designing the alleviation interventions/postinjury rehabilitation measures for adults with HHcy.

Neuron specific reduction in CuZnSOD is not sufficient to initiate a full sarcopenia phenotype.

Our previous studies showed that adult (8 month) mice lacking CuZn-superoxide dismutase (CuZnSOD, Sod1KO mice) have neuromuscular changes resulting in dramatic accelerated muscle atrophy and weakness that mimics age-related sarcopenia. We have further shown that loss of CuZnSOD targeted to skeletal muscle alone results in only mild weakness and no muscle atrophy. In this study, we targeted deletion of CuZnSOD specifically to neurons (nSod1KO mice) and determined the effect on muscle mass and weakness. The nSod1KO mice show a significant loss of CuZnSOD activity and protein level in brain and spinal cord but not in muscle tissue. The masses of the gastrocnemius, tibialis anterior and extensor digitorum longus (EDL) muscles were not reduced in nSod1KO compared to wild type mice, even at 20 months of age, although the quadriceps and soleus muscles showed small but statistically significant reductions in mass in the nSod1KO mice. Maximum isometric specific force was reduced by 8-10% in the gastrocnemius and EDL muscle of nSod1KO mice, while soleus was not affected. Muscle mitochondrial ROS generation and oxidative stress measured by levels of reactive oxygen/nitrogen species (RONS) regulatory enzymes, protein nitration and F2-isoprostane levels were not increased in muscle from the nSod1KO mice. Although we did not find evidence of denervation in the nSod1KO mice, neuromuscular junction morphology was altered and the expression of genes associated with denervation acetylcholine receptor subunit alpha (AChRα), the transcription factor, Runx1 and GADD45α) was increased, supporting a role for neuronal loss of CuZnSOD initiating alterations at the neuromuscular junction. These results and our previous studies support the concept that CuZnSOD deficits in either the motor neuron or muscle alone are not sufficient to initiate a full sarcopenic phenotype and that deficits in both tissues are required to recapitulate the loss of muscle observed in Sod1KO mice.

Sarcopenia is a risk factor for elevated aminotransferase in men independently of body mass index, dietary habits, and physical activity.

BACKGROUND: Aminotransferase activity is a surrogate marker of liver injury showing strong correlations with obesity and metabolic syndrome. However, elevated aminotransferase activity is not uncommon in non-obese and non-alcoholic patients in clinical practice. AIM: To examine the relationship between sarcopenia and aminotransferase activity in a large population-based cohort. METHODS: Data from the Korean National Health and Nutrition Examinations were used. A total of 13,431 subjects were included. A whole-body dual X-ray absorptiometry scan was performed on each patient to measure total and regional muscle mass. Appendicular skeletal muscle mass indices were also obtained. RESULTS: The prevalence of sarcopenia was significantly higher in the group with elevated aminotransferase levels than in the normal liver enzyme group (males: 26.5% vs. 16.9%; females: 38.3% vs. 22.1%, p<0.05). The skeletal muscle index was negatively correlated with most cardiometabolic risk factors, including fasting glucose and cholesterol levels. The frequency of elevated aminotransferase increased in male patients with sarcopenia after adjusting for potential confounding factors including age, body mass index, fasting glucose level, dietary, and exercise habits. However, the correlation was no longer observed in women after adjusting for body mass index. CONCLUSION: Sarcopenia is a risk factor for elevated aminotransferase in men, independently of body mass index, dietary habits, and physical activity.

[Allopurinol and its role in the treatment of sarcopenia]. / Alopurinol y su papel en el tratamiento de la sarcopenia.

Xanthine oxidase (XO) is an enzyme that catalyzes the oxidation of hypoxanthine to xanthine and uric acid and plays an important role in purine catabolism. The purine analogue, allopurinol, is a well-known inhibitor of XO widely used in the clinical management of gout and conditions associated with hyperuricemia. More recent data indicate that allopurinol reduces oxidative stress and improves vascular function in several cardiometabolic diseases, prolongs exercise time in angina, and improves the efficiency of cardiac contractility in heart failure. XO also plays an important role in free radical generation during skeletal muscle contraction and thus, it has been related to the muscle damage associated to exhaustive exercise. Several research groups have shown the protective effect of allopurinol in the prevention of this type of damage. Based on this background, a critical overview is presented on the possible role of allopurinol in the treatment of sarcopenia, a geriatric syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength with a risk of adverse outcomes, such as physical disability, poor quality of life and death.

The effects of age and muscle contraction on AMPK activity and heterotrimer composition.

Sarcopenia is characterized by increased skeletal muscle atrophy due in part to alterations in muscle metabolism. AMP-activated protein kinase (AMPK) is a master regulator of skeletal muscle metabolic pathways which regulate many cellular processes that are disrupted in old-age. Functional AMPK is a heterotrimer composed of α, ß and γ subunits, and each subunit can be represented in the heterotrimer by one of two (α1/α2, ß1/ß2) or three (γ1/γ2/γ3) isoforms. Altered isoform composition affects AMPK localization and function. Previous work has shown that overall AMPK activation with endurance-type exercise is blunted in old vs. young skeletal muscle. However, details regarding the activation of the specific isoforms of AMPK, as well as the heterotrimeric composition of AMPK in old skeletal muscle, are unknown. Our purpose here, therefore, was to determine the effect of old-age on 1) the activation of the α1 and α2 catalytic subunits of AMPK in skeletal muscle by a continuous contraction bout, and 2) the heterotrimeric composition of skeletal muscle AMPK. We studied gastrocnemius (GAST) and tibialis anterior (TA) muscles from young adult (YA; 8months old) and old (O; 30months old) male Fischer344×Brown Norway F1 hybrid rats after an in situ bout of endurance-type contractions produced via electrical stimulation of the sciatic nerve (STIM). AMPKα phosphorylation and AMPKα1 and α2 activities were unaffected by age at rest. However, AMPKα phosphorylation and AMPKα2 protein content and activity were lower in O vs. YA after STIM. Conversely, AMPKα1 content was greater in O vs. YA muscle, and α1 activity increased with STIM in O but not YA muscles. AMPKγ3 overall concentration and its association with AMPKα1 and α2 were lower in O vs. YA GAST. We conclude that activation of AMPKα1 is enhanced, while activation of α2 is suppressed immediately after repeated skeletal muscle contractions in O vs. YA skeletal muscle. These changes are associated with changes in the AMPK heterotrimer composition. Given the known roles of AMPK α1, α2 and γ3, this may contribute to sarcopenia and associated muscle metabolic dysfunction.

[Activity of the enzymes which take part in aldehyde catabolism in the mitochondria of skeletal muscle in rats of different ages and its modulation during stress].

The purpose of this study was a comparative investigation of activity of enzymes, which take part in utilization of endogenous aldehydes in mitochondrial fraction of femoral muscle in intact and immobilized rats of different age. It has been shown that 12-months-old (adult) rats have high basal levels of NAD-aldehyde dehydrogenase, NADH-aldehyde reductase and glutathione transferase activity in mitochondrial fraction of femoral muscle. An increased of NAD-aldehyde dehydrogenase activity emerges during immobilization stress in adult rats. These changes contribute to enhancing the effectiveness of utilization of carbonyl products of free radical oxidation in mitochondria of skeletal muscle of 12-months-old rats during stress. Immobilization of old and pubertal rats, is accompanied by a certain arise in metabolic preconditions, leading to accumulation of endogenous aldehydes in mitochondria, and, as a result, to the injury of muscular fibers and an increase in manifestation of sarcopenia.