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Skeletal muscle mitochondrial function is the biggest component of whole-body energy output. Mitochondrial energy production during exercise is impaired in vitamin D-deficient subjects. In cultured myotubes, loss of vitamin D receptor (VDR) function decreases mitochondrial respiration rate and ATP production from oxidative phosphorylation. We aimed to examine the effects of vitamin D deficiency and supplementation on whole-body energy expenditure and muscle mitochondrial function in old rats, old mice, and human subjects. To gain further insight into the mechanisms involved, we used C2C12 and human muscle cells and transgenic mice with muscle-specific VDR tamoxifen-inducible deficiency. We observed that in vivo and in vitro vitamin D fluctuations changed mitochondrial biogenesis and oxidative activity in skeletal muscle. Vitamin D supplementation initiated in older people improved muscle mass and strength. We hypothesize that vitamin D supplementation is likely to help prevent not only sarcopenia but also sarcopenic obesity in vitamin D-deficient subjects.

Background Low skeletal muscle index (SMI) in metastatic colorectal cancer (mCRC) patients is associated with poor outcomes. The prognostic impact of SMI changes during consecutive palliative systemic treatments is unknown. Methods This is a retrospective analysis of the phase 3 CAIRO3 study. The CAIRO3 study randomized 557 patients between maintenance capecitabine + bevacizumab (CAP‐B) or observation, after six cycles capecitabine + oxaliplatin + bevacizumab (CAPOX‐B). Upon first disease progression (PD1), CAPOX‐B was reintroduced until second progression (PD2). SMI was assessed by computed tomography (CT) (total 1355 scans). SMI and body mass index (BMI) changes were analyzed for three time‐periods; p1: during initial CAPOX‐B, p2: randomization to PD1, and p3: PD1 to PD2. The association between absolute and change in SMI and BMI (both per 1 standard deviation) during p1‐p3, with PD1, PD2, and survival was studied by Cox regression models. Results This analysis included 450 of the 557 patients randomized in the CAIRO3 study. Mean SMI decreased during p1: mean −0.6 SMI units [95% CI −1.07;‐0.26] and p3: −2.2 units [−2.7;‐1.8], whereas during p2, SMI increased + 1.2 units [0.8‐1.6]. BMI changes did not reflect changes in SMI. SMI loss during p2 and p3 was significantly associated with shorter survival (HR 1.19 [1.09‐1.35]; 1.54 [1.31‐1.79], respectively). Sarcopenia at PD1 was significantly associated with early PD2 (HR 1.40 [1.10‐1.70]). BMI loss independent of SMI loss was only associated with shorter overall survival during p3 (HR 1.35 [1.14‐1.63]). Conclusions In mCRC patients, SMI loss during palliative systemic treatment was related with early disease progression and reduced survival. BMI did not reflect changes in SMI and could not identify patients at risk of poor outcome during early treatment lines.

© 2018 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Background Increasing evidence suggests that severe skeletal muscle index (SMI) loss (sarcopenia) is associated with poor overall survival in metastatic colorectal cancer patients, but its mechanisms are unknown. We recently found, using data of the randomized phase 3 CAIRO3 study, that SMI loss was related with shorter time to disease progression and overall survival during first‐line maintenance treatment with capecitabine + bevacizumab (CAP‐B) or observation and during more intensive capecitabine + oxaliplatin + bevacizumab (CAPOX‐B) reintroduction treatment. As a potential risk factor for reduced survival, we explored whether sarcopenia and SMI loss were associated with dose‐limiting toxicities (DLTs) during CAP‐B and CAPOX‐B. Methods Sarcopenia status and SMI loss were assessed by using consecutive computed tomography scans. DLTs were defined as any dose delay/reduction/discontinuation of systemic treatment because of reported CTCAE (version 3.0) toxicities at the start or during treatment. Poisson regression models were used to study whether sarcopenia and body mass index (BMI) at the start of treatment and SMI and BMI loss during treatment were associated with DLTs. Results One hundred eighty‐two patients (mean age 63.0 ± 8.8 years, 37% female) received CAP‐B, and 232 patients (mean age 63.0 ± 9.0 years, 34% female) received CAPOX‐B. At the start of CAP‐B and CAPOX‐B, 54% and 46% of patients were sarcopenic, respectively. Mean BMI was lower in sarcopenic patients, although patients were on average still overweight (sarcopenic vs. non‐sarcopenic at the start of CAP‐B 25.0 ± 3.9 vs. 26.7 ± 4.1 and CAPOX‐B 25.8 ± 3.8 vs. 27.1 ± 3.8 kg/m2). Sarcopenia at the start of CAP‐B was not associated with DLTs [relative risk 0.87 (95% confidence interval 0.64–1.19)], whereas patients with >2% SMI loss had a significantly higher risk of DLTs [1.29 (1.01–1.66)]. At the start of subsequent CAPOX‐B, 25% of patients received a dose reduction, and the risk of dose reduction was significantly higher for patients with preceding SMI loss [1.78 (1.06–3.01)] or sarcopenia [1.75 (1.08–2.86)]. After the received dose reductions, sarcopenia or SMI loss was not significantly associated with a higher risk of DLTs during CAPOX‐B [sarcopenia vs. non‐sarcopenic: 0.86 (0.69–1.08) and SMI loss vs. stable/gain: 0.83 (0.65–1.07)]. In contrast, BMI (loss) at the start or during either treatment was not associated with an increased risk of DLTs. Conclusions In this large longitudinal study in metastatic colorectal cancer patients during palliative systemic treatment, sarcopenia and/or muscle loss was associated with an increased risk of DLTs. BMI was not associated with DLTs and could not detect sarcopenia or SMI loss. Prospective (randomized) studies should reveal whether normalizing chemotherapeutic doses to muscle mass or muscle mass preservation (by exercise and nutritional interventions) increases chemotherapeutic tolerance and improves survival.

Antioxidant (AOX) deficiencies are commonly observed in older adults and oxidative stress has been suggested to contribute to sarcopenia. Here we investigate if 1) low levels of dietary antioxidants had a negative impact on parameters of muscle mass, function and quality, and 2) to study if nutritional interventions with AOX and/or leucine-enriched whey protein could improve these muscle parameters in aged mice. 18-months-old mice were fed a casein-based antioxidant-deficient (lowox) diet or a casein-based control-diet (CTRL) for 7 months. During the last 3 months, lowox-mice were subjected to either: a) continued lowox, b) supplementation with vitamin A/E, Selenium and Zinc (AOX), c) substitution of casein with leucine-enriched whey protein (PROT) or d) a combination of both AOX and PROT (TOTAL). After 7 months lowox-mice displayed lower muscle strength and more muscle fatigue compared to CTRL. Compared to lowox-mice, PROT-mice showed improved muscle power, grip strength and less muscle fatigue. AOX-mice showed improved oxidative status, less muscle fatigue, improved grip strength and mitochondrial dynamics compared to lowox-mice. The TOTAL-mice showed the combined effects of both interventions compared to lowox-mice. In conclusion, nutritional intervention with AOX and/or leucine-enriched whey protein can play a role in improving muscle health in a AOX-deficient mouse model.

Background: Evidence is increasing that severe skeletal muscle (SM) loss (sarcopenia) is associated with reduced overall survival (OS) in mCRC pts. We recently found, using data of the randomized phase 3 CAIRO3 study (Lancet, 2015), that SM loss was related to shorter time to progression during first line maintenance treatment (Tx) with capecitabine+bevacizumab (CAP-B) or observation. Subsequently, SM loss during more intensive reinduction Tx by adding oxaliplatin (CAPOX-B) was associated to shorter overall survival (ASCO, 2017). As a potential risk factor for reduced survival we explored whether sarcopenia was associated with dose reductions at start of CAPOX-B reinduction Tx and dose limiting toxicities (DLT) during CAPOX-B reinduction Tx. Methods: Here, CAIRO3 pts were included who received CAPOX-B reinduction Tx. DLT were defined as any dose delay, reduction, or discontinuation of systemic treatment because of reported CTCAE (v3.0) toxicities at start or during Tx. Poisson regression models adjusted for relevant confounders were used to study the association between sarcopenia and DLT. Results: A total of 254 pts received CAPOX-B reinduction Tx. 39% of pts were sarcopenic and compared to normal SM pts we found no statistically significant differences in age and sex (sarcopenic vs normal SM: mean age 63.6±9.1 vs 61.9±8.5 yrs, p=.20 and 39% vs 31% females p=.31). BMI was significantly lower in sarcopenic pts, but pts were on average still overweight (25.9±3.8 vs 27.2±3.8 p=.01). Overall, 67% experienced ≥1 DLT. At start of CAPOX-B, 25% had already received a dose reduction and the risk of dose reduction at start was significantly higher for sarcopenic compared to normal SM pts (RR 1.8 95%CI 1.08-2.90). Despite more frequent dose reductions at start, sarcopenic pts did not have a significantly lower risk of DLT during CAPOX-B Tx (RR sarcopenic vs normal SM pts 0.86 95% CI 0.46-1.45). Conclusions: Sarcopenia was significantly associated with dose reductions at start of CAPOX-B reinduction Tx, and not with DLT during CAPOX-B reinduction Tx. Possible explanations for dose reductions at start might be more frequent toxicities during previous Tx including neuropathy.

Background: A promising strategy to help older adults preserve or build muscle mass is to optimize muscle anabolism through providing an adequate amount of high-quality protein at each meal.Objective: This "proof of principle" study investigated the acute effect of supplementing breakfast with a vitamin D and leucine-enriched whey protein medical nutrition drink on postprandial muscle protein synthesis and longer-term effect on muscle mass in healthy older adults.Methods: A randomized, placebo-controlled, double-blind study was conducted in 24 healthy older men [mean ± SD: age 71 ± 4 y; body mass index (in kg/m2) 24.7 ± 2.8] between September 2012 and October 2013 at the Unit of Human Nutrition, University of Auvergne, Clermont-Ferrand, France. Participants received a medical nutrition drink [test group; 21 g leucine-enriched whey protein, 9 g carbohydrates, 3 g fat, 800 IU cholecalciferol (vitamin D3), and 628 kJ] or a noncaloric placebo (control group) before breakfast for 6 wk. Mixed muscle protein fractional synthesis rate (FSR) was measured at week 0 in the basal and postprandial state, after study product intake with a standardized breakfast with the use of l-[2H5]-phenylalanine tracer methodology. The longer-term effect of the medical nutrition drink was evaluated by measurement of appendicular lean mass, representing skeletal muscle mass at weeks 0 and 6, by dual-energy X-ray absorptiometry.Results: Postprandial FSR (0-240 min) was higher in the test group than in the control group [estimate of difference (ED): 0.022%/h; 95% CI: 0.010%/h, 0.035%/h; ANCOVA, P = 0.001]. The test group gained more appendicular lean mass than the control group after 6 wk (ED: 0.37 kg; 95% CI: 0.03, 0.72 kg; ANCOVA, P = 0.035), predominantly as leg lean mass (ED: 0.30 kg; 95% CI: 0.03, 0.57 kg; ANCOVA, P = 0.034).Conclusions: Supplementing breakfast with a vitamin D and leucine-enriched whey protein medical nutrition drink stimulated postprandial muscle protein synthesis and increased muscle mass after 6 wk of intervention in healthy older adults and may therefore be a way to support muscle preservation in older people. This trial was registered at www.trialregister.nl as NTR3471.

The authors gratefully acknowledge all members of the animal facilities from Theix's INRA center for their valuable assistance in conducting this study; We investigated the impact of vitamin D deficiency and repletion on muscle anabolism in old rats. Animals were fed a control (1 IU vitamin D3/g, ctrl, n=20) or a vitamin D-depleted diet (VDD; 0 IU, n=30) for 6 months. A subset was thereafter sacrificed in the control (ctrl6) and depleted groups (VDD6). Remaining control animals were kept for 3 additional months on the same diet (ctrl9), while a part of VDD rats continued on a depleted diet (VDD9) and another part was supplemented with vitamin D (5 IU, VDS9). The ctr16 and VDD6 rats and the ctr19, VDD9 and VDS9 rats were 21 and 24 months old, respectively. Vitamin D status, body weight and composition, muscle strength, weight and lipid content were evaluated. Muscle protein synthesis rate (fractional synthesis rate; FSR) and the activation of controlling pathways were measured. VDD reduced plasma 25(OH)-vitamin D, reaching deficiency (