Changes in IL-15 expression and death-receptor apoptotic signaling in rat gastrocnemius muscle with aging and life-long calorie restriction

TNF-α-mediated apoptosis is enhanced in aged rodent muscles, suggesting that this pathway may be involved in sarcopenia. Interleukin-15 (IL-15), a muscle-derived anabolic cytokine, mitigates muscle wasting and apoptosis in cachectic rats. This effect is thought to occur through inhibition of TNF-α-triggered apoptosis. We investigated IL-15 signaling and the TNF-α-mediated pathway of apoptosis in the gastrocnemius muscle of Fischer344xBrown Norway rats across the ages of 8, 18, 29 and 37 months, in relation to life-long calorie restriction (CR, 40% calorie intake reduction). Aging caused loss of muscle mass and increased apoptotic DNA fragmentation, which were mitigated by CR. Protein levels of IL-15 and mRNA abundance of IL-15 receptor α-chain decreased in senescent ad libitum (AL) fed rats, but were maintained in CR rodents. Elevations of TNF-α, TNF-receptor 1, cleaved caspase-8 and -3 were observed at advanced age in AL rats. These changes were prevented or mitigated by CR. Our results indicate that aging is associated with decreased IL-15 signaling in rat gastrocnemius muscle, which may contribute to sarcopenia partly through enhanced TNF-α-mediated apoptosis. Preservation of IL-15 signaling by CR may therefore represent a further mechanism contributing to the anti-aging effect of this dietary intervention in skeletal muscle.     

Contributions of force and velocity to improved power with progressive resistance training in young and older adults

We investigated the effects of age on changes in the force and velocity components of knee extension (KE) power during 16 weeks of traditional progressive resistance training (PRT). Thirty-one young (27 ± 1 years, 16 men, 15 women) and 30 older (64 ± 1 years, 14 men, 16 women) adults trained by KE, leg press, and squat 3 days/week. PRT consisted of three sets with an appropriate load for 8–12 repetitions to fatigue. Testing occurred at baseline, 8, and 16 weeks. Thigh lean mass (TLM) was measured by DEXA. KE load–power and load–velocity curves were generated from peak concentric contractions against loads equivalent to 20, 30, 40, 50, and 60% maximum voluntary isometric contraction (MVC) force. Quadriceps neural activation relative to maximum was assessed during a sit-to-stand task. Participants increased KE 1RM (P < 0.05) by 8 weeks with young adults also increasing strength from 8 to 16 weeks. Adjusting for TLM, all groups increased KE specific strength (P < 0.05). MVC improved by 8 weeks in older adults and by 16 weeks in young subjects (P < 0.05). Neural activation requirements during standing and sitting declined in older adults by 8 weeks (P < 0.05). The KE load–power curve improved for all groups (P < 0.05) by 8 weeks with only young adults improving from 8 to 16 weeks. Peak concentric velocity increased only in older adults (P < 0.05). Training improvements in power resulted primarily from increases in strength both early and late for young adults while older adults realized early improvements in both strength and peak concentric velocity. Grants: This study was supported by National Institute on Aging Grant R01 AG017896 (MMB), Department of Veterans’ Affairs Merit Grant (MMB), and General Clinical Research Center Grant M01 RR00032.     

Prognostic role of sarcopenia in metastatic colorectal cancer patients during first-line chemotherapy: A retrospective study

BACKGROUNDSarcopenia is a condition characterized by decreased skeletal muscle mass due to physiological ageing or to a concomitant disease such as neoplasia. In cancer patients, a low lean body mass is suggested to be a negative prognostic factor for survival and for the development of dose-limiting chemotherapy toxicities irrespective of disease stage. AIMTo evaluate the prognostic role of sarcopenia in patients with metastatic colorectal cancer (mCRC) undergoing first-line chemotherapy.METHODSOur retrospective analysis included 56 mCRC patients who received first-line chemotherapy from 2014 to 2017 at the Medical Oncology Unit of our hospital. Computerized scans were performed before starting chemotherapy and at the first disease reassessment. Sarcopenia was assessed using the skeletal mass index = muscle area in cm²/(height in m²) calculated at the L3 vertebra. Overall survival and objective response rate were evaluated. Toxicities were analyzed during the first four cycles of therapy and graded according to Common Terminology Criteria for Adverse Events version 4.0. A loss of skeletal muscle mass ≥ 5% was considered indicative of deterioration in muscle condition.RESULTSMedian age was 67 years and 35.7% of patients were ≥ 70 years old. Fourteen patients (25%) were sarcopenic at baseline computed tomography (CT) scan (7/33 men; 7/23 women); 5/14 sarcopenic patients were ≥ 70 years old. Median follow-up was 26.8 mo (3.8-66.8 mo) and median overall survival was 27.2 mo (95%CI: 23.3-37.3). Sarcopenia was not correlated to overall survival (P = 0.362), to higher toxicities reported during the first 4 cycles of chemotherapy (P = 1.0) or to response to treatment (P = 0.221). At the first disease reassessment, a skeletal muscle loss (SML) ≥ 5% was found in 17 patients (30.3%) 3 of whom were already sarcopenic at baseline CT scan, while 7 patients became sarcopenic. SML was not correlated to overall survival (P = 0.961). No statistically significant correlation was found between baseline sarcopenia and age (P = 1.0), body mass index (P = 0.728), stage at diagnosis (P = 0.355) or neutrophil/lymphocyte ratio (P = 0.751).CONCLUSIONNeither baseline sarcopenia nor SML affected survival. In addition, baseline sarcopenia was not related to worse treatment toxicity. However, these results must be interpreted with caution due to the limited sample size.     

肌少症对食管鳞癌术后复发患者放化疗不良反应及预后影响

目的 探讨基于定位CT分析肌少症对食管鳞癌术后复发患者放化疗期间不良反应及预后的影响。方法 回顾性分析2016—2017年于淮安市第一人民医院行放化疗的147例食管鳞癌术后局部复发患者,依据模拟定位CT勾画计算主动脉弓上缘水平横断面双侧胸肌面积（PMA）。PMA身高校正（PMA/身高²）得出胸肌指数（PMI）。将男女患者分别依据PMI三分位数分组,其中低PMI者（男性<11.55 cm²/m²,女性<8.69 cm²/m²）为肌少症组。比较肌少症组与非肌少症组患者治疗期间不良反应发生率及1年和3年总生存（OS）率的差异。结果 147例患者中49例（33.3%）存在肌肉减少,该类患者3‐4级不良反应发生率显著高于非肌少症患者（40.8%∶18.4%,P=0.005）。肌少症患者1年和3年OS（61.2%和10.2%）显著低于非肌少症患者（82.7%和28.6%）,差异具有统计学意义（P<0.001）,多因素分析证实肌少症是预测不良预后的独立危险因素（P<0.001）。结论 基于定位CT获得的PMI在诊断肌少症方面具有较好的临床价值,可能可以作为诊断肌少症的新工具。     

Is handgrip strength a marker of muscle and physical function of the lower limbs? Sex differences in older adults with obesity

Background and aimsIn this cross-sectional study we investigate the association between handgrip strength (HGS) and muscle function of the lower limbs and the predictors of the appendicular lean mass index (ALMI) in older adults with obesity of both sexes.Methods and resultsEighty-four older (67 ± 5 years) men (N = 44) and women (N = 40) with obesity (body mass index (BMI) 33 ± 4 kg/m²) performed: the HGS, isokinetic knee extensors (KE) and flexors (KF) muscle strength and power and Short Physical Performance Battery (SPPB). The correlation between HGS and lower limbs muscle function was evaluated, and four multiple hierarchical linear models were built to assess the contribution of each ALMI predictor (i.e., HGS, BMI, SPPB, muscle strength and power).In men, HGS was weakly-to-moderately associated (p < 0.05) with KE, KF muscle function and physical performance. In women, HGS showed a weak association (p < 0.05) with KE muscle function. The significant predictors of ALMI were only the BMI in women, whereas in the group of men BMI, KE maximal strength and power better explain the variance in ALMI than HGS alone.ConclusionOur results suggest that HGS should not be used alone as a marker of lower muscle nor physical function. Sex differences exist with the BMI that is a contributor of ALMI both in men and women. However, at least in the group of men, markers related to strength and power of the lower limbs can better describe variations in ALMI compared to HGS in this kind of population.Clinical trial registrationNA.     

Older men are more fatigable than young when matched for maximal power and knee extension angular velocity is unconstrained

The underlying factors related to the divergent findings of age-related fatigue for dynamic tasks are not well understood. The purpose here was to investigate age-related fatigability and recovery between a repeated constrained (isokinetic) and an unconstrained velocity (isotonic) task, in which participants performed fatiguing contractions at the velocity (isokinetic) or resistance (isotonic) corresponding with maximal power. To compare between tasks, isotonic torque–power relationships were constructed prior to and following both fatiguing tasks and during short-term recovery. Contractile properties were recorded from 9 old (~75 years) and 11 young (~25 years) men during three testing sessions. In the first session, maximal power was assessed, and sessions 2 and 3 involved an isokinetic or an isotonic concentric fatigue task performed until maximal power was reduced by 40 %. Compared with young, the older men performed the same number of contractions to task failure for the isokinetic task (~45 contractions), but 20 % fewer for the isotonic task (p < 0.05). Regardless of age and task, maximal voluntary isometric contraction strength, angular velocity, and power were reduced by ~30, ~13, and ~25 %, respectively, immediately following task failure, and only isometric torque was not recovered fully by 10 min. In conclusion, older men are more fatigable than the young when performing a repetitive maximal dynamic task at a relative resistance (isotonic) but not an absolute velocity (isokinetic), corresponding to maximal power.