BackgroundCancer cachexia is largely irreversible, at least via nutritional means, and responsible for 20–40% of cancer‐related deaths. Therefore, preventive measures are of primary importance; however, little is known about muscle perturbations prior to onset of cachexia. Cancer cachexia is associated with mitochondrial degeneration; yet, it remains to be determined if mitochondrial degeneration precedes muscle wasting in cancer cachexia. Therefore, our purpose was to determine if mitochondrial degeneration precedes cancer‐induced muscle wasting in tumour‐bearing mice.MethodsFirst, weight‐stable (MinStable) and cachectic (MinCC) Apc Min/+ mice were compared with C57Bl6/J controls for mRNA contents of mitochondrial quality regulators in quadriceps muscle. Next, Lewis lung carcinoma (LLC) cells or PBS (control) were injected into the hind flank of C57Bl6/J mice at 8 week age, and tumour allowed to develop for 1, 2, 3, or 4 weeks to examine time course of cachectic development. Succinate dehydrogenase stain was used to measure oxidative phenotype in tibialis anterior muscle. Mitochondrial quality and function were assessed using the reporter MitoTimer by transfection to flexor digitorum brevis and mitochondrial function/ROS emission in permeabilized adult myofibres from plantaris. RT‐qPCR and immunoblot measured the expression of mitochondrial quality control and antioxidant proteins. Data were analysed by one‐way ANOVA with Student–Newman–Kuels post hoc test.ResultsMinStable mice displayed ~50% lower Pgc‐1α, Pparα, and Mfn2 compared with C57Bl6/J controls, whereas MinCC exhibited 10‐fold greater Bnip3 content compared with C57Bl6/J controls. In LLC, cachectic muscle loss was evident only at 4 weeks post‐tumour implantation. Oxidative capacity and mitochondrial content decreased by ~40% 4 weeks post‐tumour implantation. Mitochondrial function decreased by ~25% by 3 weeks after tumour implantation. Mitochondrial degeneration was evident by 2 week LLC compared with PBS control, indicated by MitoTimer red/green ratio and number of pure red puncta. Mitochondrial ROS production was elevated by ~50 to ~100% when compared with PBS at 1–3 weeks post‐tumour implantation. Mitochondrial quality control was dysregulated throughout the progression of cancer cachexia in tumour‐bearing mice. In contrast, antioxidant proteins were not altered in cachectic muscle wasting.ConclusionsFunctional mitochondrial degeneration is evident in LLC tumour‐bearing mice prior to muscle atrophy. Contents of mitochondrial quality regulators across Apc Min/+ and LLC mice suggest impaired mitochondrial quality control as a commonality among pre‐clinical models of cancer cachexia. Our data provide novel evidence for impaired mitochondrial health prior to cachectic muscle loss and provide a potential therapeutic target to prevent cancer cachexia.

While skeletal muscle mass is an established primary outcome related to understanding cancer cachexia mechanisms, considerable gaps exist in our understanding of muscle biochemical and functional properties that have recognized roles in systemic health. Skeletal muscle quality is a classification beyond mass, and is aligned with muscle's metabolic capacity and substrate utilization flexibility. This supplies an additional role for the mitochondria in cancer-induced muscle wasting. While the historical assessment of mitochondria content and function during cancer-induced muscle loss was closely aligned with energy flux and wasting susceptibility, this understanding has expanded to link mitochondria dysfunction to cellular processes regulating myofiber wasting. The primary objective of this article is to highlight muscle mitochondria and oxidative metabolism as a biological target of cancer cachexia and also as a cellular regulator of cancer-induced muscle wasting. Initially, we examine the role of muscle metabolic phenotype and mitochondria content in cancer-induced wasting susceptibility. We then assess the evidence for cancer-induced regulation of skeletal muscle mitochondrial biogenesis, dynamics, mitophagy, and oxidative stress. In addition, we discuss environments associated with cancer cachexia that can impact the regulation of skeletal muscle oxidative metabolism. The article also examines the role of cytokine-mediated regulation of mitochondria function regulation, followed by the potential role of cancer-induced hypogonadism. Lastly, a role for decreased muscle use in cancer-induced mitochondrial dysfunction is reviewed.

The effect of interrepetition rest (IRR) periods on power output during performance of multiple sets of power cleans is unknown. It is possible that IRR periods may attenuate the decrease in power output commonly observed within multiple sets. This may be of benefit for maximizing improvements in power with training. This investigation involved 10 college-aged men with proficiency in weightlifting. The subjects performed 3 sets of 6 repetitions of power cleans at 80% of their 1 repetition maximum with 0 (P0), 20 (P20), or 40 seconds (P40) of IRR. Each protocol (P0, P20, P40) was performed in a randomized order on different days each separated by at least 72 hours. The subjects performed the power cleans while standing on a force plate with 2 linear position transducers attached to the bar. Peak power, force, and velocity were obtained for each repetition and set. Peak power significantly decreased by 15.7% during P0 in comparison with a decrease of 5.5% (R1: 4,303 ± 567 W, R6: 4,055 ± 582 W) during P20 and a decrease of 3.3% (R1: 4,549 ± 659 W, R6: 4,363 ± 476 W) during P40. Peak force significantly decreased by 7.3% (R1: 2,861 ± 247 N, R6: 2,657 ± 225 N) during P0 in comparison with a decrease of 2.7% (R1: 2,811 ± 327 N, R6: 2,730 ± 285 N) during P20 and an increase of 0.4% (R1: 2,861 ± 323 N, R6: 2,862 ± 280 N) during P40. Peak velocity significantly decreased by 10.2% (R1: 1.97 ± 0.15 m·s(-1), R6: 1.79 ± 0.11 m·s(-1)) during P0 in comparison with a decrease of 3.8% (R1: 1.89 ± 0.13 m·s(-1), R6: 1.82 ± 0.12 m·s(-1)) during P20 and a decrease of 1.7% (R1: 1.93 ± 0.17 m·s(-1), R6: 1.89 ± 0.14 m·s(-1)) during P40. The results demonstrate that IRR periods allow for the maintenance of power in the power clean during a multiple set exercise protocol and that this may have implications for improved training adaptations.

PURPOSE The purpose of this study was to determine the effects of early outpatient exercise on muscle mass, function, and fractional synthetic rate in severely burned children. METHODS Forty-seven children with ≥40 % total body surface area burn performed 12-weeks standard of care rehabilitation (SOC: N=23) or rehabilitative exercise training (RET: N=24) immediately following hospital discharge. Dual-energy X-ray absorptiometry was used to assess lean body mass (LBM) at discharge, post-treatment, and 12 months post-burn. Muscle function was evaluated with a Biodex Isokinetic Dynamometer and peak aerobic fitness (VO2peak) measured using a modified Bruce treadmill protocol post-treatment. Stable isotope infusion studies were performed in a subset of patients (SOC: N=13; RET: N=11) at discharge and post-treatment to determine mixed-muscle fractional synthetic rate. RESULTS Relative peak torque (RET: 138 ± 9 N · m · kg−1 vs SOC: 106 ± 9 N · m · kg−1) and VO2peak (RET: 32 ± 1 ml · kg−1 · min−1 vs SOC: 28 ± 1 ml · kg−1 · min−1) was greater post-treatment with RET compared to SOC. In addition, RET increased whole-body (9 ± 2%) and leg (17 ± 3%) LBM compared to SOC. Furthermore, the percentage change in whole-body (18 ± 3%) and leg (31 ± 4%) LBM from discharge to 12 months post-burn was greater with RET compared to SOC. Muscle fractional synthetic rate decreased from discharge to post-treatment in both groups (6.9 ± 1.1% · d−1 vs 3.4 ± 0.4% · d−1); however no differences were observed between treatment groups at each time-point. CONCLUSIONS Early outpatient exercise training implemented at hospital discharge represents an effective intervention to improve muscle mass and function following severe burn injury.

The purpose of this study was to examine the effects of inter-repetition rest (IRR) on ratings of perceived exertion (RPE) in the power clean exercise in a multiple set protocol using peak power as an indication of fatigue. Ten resistance-trained males participated in four testing sessions which consisted of determination of a one repetition maximum (1RM) in the power clean exercise (session 1) and performance of three sets of six repetitions at 80% of 1RM with 0 (P0), 20 (P20), or 40 s (P40) IRR (sessions 2-4). Fatigue during all three conditions was indicated by a significant decrease in power of 9.0% (P0), 3.0% (P20) and 2.1% (P40), respectively. Significant difference in the rate of power decrease in P40 indicates less fatigue in comparison to P0 and P20. P40 resulted in a significantly lower RPE compared to P0 and P20 (7.43 ± 0.34, 6.46 ± 0.47, and 5.30 ± 0.55, respectively). RPE increased significantly (p ≤ 0.01) within each set (5.26 ± 0.37, 6.46 ± 0.44, and 7.46 ± 0.53; sets 1, 2, and 3, respectively). Significant difference in average RPE between the conditions indicates that RPE is not a determinant of intensity (% of 1RM) but the rate of fatigue (decreases in peak power). In addition, the fact that RPE increased between sets 1, 2 and 3 during all conditions support the same conclusion. The results demonstrate that increasing IRR in power clean training decreases the perception of effort and is inversely related to the rate of fatigue.