Metastatic or xenograft colorectal cancer models induce divergent anabolic deficits and expression of pro-inflammatory effectors of muscle wasting in a tumor-type-dependent manner.

We investigated the impact of tumor burden on muscle wasting in metastatic (m) and xenograft (x) models of colorectal cancer (CRC). Male Nod SCID γ and CD2F1 mice were injected subcutaneously or intrasplenically with HCT116 or C26 tumor cells, respectively. CRC tumors resulted in significant muscle wasting regardless of tumor type or model, although muscle loss was exacerbated in mHCT116 hosts. The mHCT116 model decreased ribosomal (r)RNA content and rDNA transcription, whereas the mC26 model showed no loss of rRNA and the upregulation of rDNA transcription. The xHCT116 model reduced mTOR, RPS6, and 4E-BP1 phosphorylation, whereas the mHCT116 model had a similar effect on RPS6 and 4E-BP1 without altering mTOR phosphorylation. The C26 models caused a reduction in 4E-BP1 phosphorylation independent of mTOR. Muscle interleukin (IL)-6 mRNA was elevated in all models except xHCT116, and the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) mRNA was induced only in the mC26 model. IL-1ß mRNA increased in all groups with greater expression in metastatic relative to the xenograft model regardless of tumor types. Our findings indicate that HCT116 tumor burden results in more drastic muscle wasting and anabolic deficits, whereas C26 tumor burden causes similar muscle wasting but exhibits a divergent proinflammatory phenotype. These results highlight potentially important divergence in the pathogenesis of muscle wasting among preclinical models of CRC and demonstrate that tumor burden plays a role in determining anabolic deficits and the expression of proinflammatory effectors of muscle wasting in a tumor-type-dependent manner.NEW & NOTEWORTHY We provide evidence demonstrating that colorectal tumor burden plays a role in determining anabolic deficits and the expression of proinflammatory effectors of muscle wasting in a tumor-type-dependent manner.

LP07 and LLC preclinical models of lung cancer induce divergent anabolic deficits and expression of pro-inflammatory effectors of muscle wasting.

Preclinical models have been instrumental to elucidate the mechanisms underlying muscle wasting in lung cancer (LC). We investigated anabolic deficits and the expression of proinflammatory effectors of muscle wasting in the LP07 and Lewis lung carcinoma (LLC) tumor models. Tumor growth resulted in significant weakness in LP07 but not in LLC mice despite similar reductions in gastrocnemius muscle mass in both models. The LP07 tumors caused a reduction in ribosomal (r)RNA and a decrease in rRNA gene (rDNA) transcription elongation, whereas no changes in ribosomal capacity were evident in LLC tumor-bearing mice. Expression of RNA Polymerase I (Pol I) elongation-associated subunits Polr2f, PAF53, and Znrd1 mRNAs was significantly elevated in the LP07 model, whereas Pol I elongation-related factors FACT and Spt4/5 mRNAs were elevated in the LLC mice. Reductions in RPS6 and 4E-BP1 phosphorylation were similar in both models but were independent of mTOR phosphorylation in LP07 mice. Muscle inflammation was also tumor-specific, IL-6 and TNF-α mRNA increased with LLC tumors, and upregulation of NLRP3 mRNA was independent of tumor type. In summary, although both models caused muscle wasting, only the LP07 model displayed muscle weakness with reductions in ribosomal capacity. Intracellular signaling diverged at the mTOR level with similar reductions in RPS6 and 4E-BP1 phosphorylation regardless of tumor type. The increase in proinflammatory factors was more pronounced in the LLC model. Our results demonstrate novel divergent anabolic deficits and expression of proinflammatory effectors of muscle wasting in the LP07 and LLC preclinical models of lung cancer.NEW & NOTEWORTHY We provide novel data demonstrating significant divergence in anabolic deficits and the expression of proinflammatory effectors of muscle wasting consequent to different lung-derived tumors.

Chemotherapy agents reduce protein synthesis and ribosomal capacity in myotubes independent of oxidative stress.

Chemotherapeutic agents (CAs) are first-line antineoplastic treatments against a wide variety of cancers. Despite their effectiveness in halting tumor progression, side effects associated with CAs promote muscle loss by incompletely understood mechanisms. To address this problem, we first identified how oxidative stress impairs protein synthesis in C2C12 myotubes. Transient elevations in reactive oxygen species (ROS) resulted in protein synthesis deficits and reduced ribosomal (r)RNA levels. Oxidative stress did not reduce rRNA gene (rDNA) transcription, but it caused an increase in rRNA and protein oxidation. To determine whether CAs affect protein synthesis independent of oxidative stress, we exposed myotubes to Paclitaxel (PTX), Doxorubicin (DXR), or Marizomib (Mzb) at doses that did result in elevated ROS levels (sub-ROS). Exposure to CAs reduced protein synthesis and rRNA levels, but unlike oxidative stress, sub-ROS exposures impaired rDNA transcription. These results indicate that although oxidative stress disrupts protein synthesis by compromising ribosomal quantity and quality, CAs at sub-ROS doses compromise protein synthesis and ribosomal capacity, at least in part, by reducing rDNA transcription. Therefore, CAs negatively impact protein synthesis by causing oxidative stress in addition to directly reducing the ribosomal capacity of myotubes in a ROS-independent manner.

Low-volume acute multi-joint resistance exercise elicits a circulating brain-derived neurotrophic factor response but not a cathepsin B response in well-trained men.

This study examined if acute multi-joint resistance exercises (RE; back squat, bench press, and deadlift) to volitional failure elicited a postexercise increase in the circulating response of biomarkers associated with neuroprotection. Thirteen males (age: 24.5 ± 3.8 years, body mass: 84.01 ± 15.44 kg, height: 173.43 ± 8.57 cm, training age: 7.1 ± 4.2 years) performed 4 sets to failure at 80% of a 1-repetition maximum on the squat, bench press, and deadlift in successive weeks. The measured biomarkers were brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), cathepsin B (CatB), and interleukin 6 (IL-6). Biomarkers were assessed immediately before and 10-min after exercise. There was a main time effect (pre-exercise: 24.00 ± 0.61 to postexercise: 27.38 ± 0.48 ng/mL; p < 0.01) for BDNF with increases in the deadlift (p = 0.01) and bench press (p = 0.01) conditions, but not in the squat condition (p = 0.21). There was a main time effect (pre-exercise: 0.87 ± 0.16 to postexercise: 2.03 ± 0.32 pg/mL; p < 0.01) for IL-6 with a significant increase in the squat (p < 0.01), but not the bench press (p = 0.88) and deadlift conditions (p = 0.24). No main time effect was observed for either CatB (p = 0.62) or IGF-1 (p = 0.56). In summary, acute multi-joint RE increases circulating BDNF. Further, this investigation is the first to report the lack of a transient change of CatB to an acute RE protocol. Novelty Low-volume RE to failure can increase BDNF. Resistance training does not confer an acute Cat B response.

The effects of eccentric phase duration on concentric outcomes in the back squat and bench press in well-trained males.

The velocity and magnitude in which the eccentric phase of an exercise is completed directly affects performance during the concentric phase. Therefore, the purpose of this research was to investigate the effects of eccentric phase duration on concentric outcomes at 60% and 80% of one-repetition maximum (1RM) in the squat and bench press. Sixteen college-aged, resistance-trained males completed 1RM testing, established normative eccentric durations, and performed fast (0.75 times normative) and slow (2.0 times normative) metronome-controlled eccentric duration repetitions. Outcome measures assessed during the concentric phase were: average concentric velocity (ACV), peak concentric velocity (PCV), rating of perceived exertion (RPE), range of motion (ROM), and barbell path. Eccentric duration was significantly and inversely correlated with ACV at 60% (r = -0.408, p = 0.004) and 80% (r = -0.477, p = 0.001) of 1RM squat. At 60% of 1RM squat, both fast and slow eccentric conditions produced greater (p < 0.001) PCV than normative duration with fast also producing greater PCV than slow (p = 0.044). Eccentric duration had no impact on RPE, ROM, or barbell path. Our results report for the first time that resistance-trained males performing a deliberately faster eccentric phase may enhance their own squat and bench press performance.

Time course of recovery is similar for the back squat, bench press, and deadlift in well-trained males.

This study examined the time course of recovery following resistance exercise sessions in the back squat, bench press, and deadlift. Twelve well-trained males (age: 24.5 ± 3.8 years, body mass: 84.01 ± 15.44 kg, training age: 7.1 ± 4.2 years) performed 4 sets to failure at 80% of a 1-repetition maximum (1RM) on the squat, bench press, and deadlift in successive weeks. The bench press was always performed in week 2 with the squat and deadlift order counterbalanced between weeks 1 and 3. Indirect muscle damage and performance fatigue was assessed immediately before and after exercise and at 24 h, 48 h, 72 h, and 96 h postexercise. Outcome measures included limb swelling, joint range of motion, delayed onset muscle soreness, average concentric velocity (ACV) at 70% of 1RM, creatine kinase, lactate dehydrogenase, and cell-free DNA (cfDNA). Most measures demonstrated a main time effect (p < 0.05) within conditions; however, no between condition (p > 0.05) differences existed. ACV decreased in the squat condition for up to 72 h (p = 0.02, -8.61%) and in the bench press (p < 0.01, -26.69%) immediately postexercise but did not decline during the deadlift condition (p > 0.05). There was a main time effect for increased cfDNA in the squat (p < 0.01) and bench press (p < 0.05), but not the deadlift (p = 0.153). Further, immediately postexercise increases in cfDNA were directly related (p < 0.05) to changes in ACV in all 3 conditions. These results suggest that the deadlift does not result in greater muscle damage and recovery time than the squat and bench press following volume-type training in well-trained men. Further, acute changes in cfDNA may predict performance during the recovery period.