Depleting Ly6G Positive Myeloid Cells Reduces Pancreatic Cancer-Induced Skeletal Muscle Atrophy

Immune cells can mount desirable anti-cancer immunity. However, some immune cells can support cancer disease progression. The presence of cancer can lead to production of immature myeloid cells from the bone marrow known as myeloid-derived suppressor cells (MDSCs). The immunosuppressive and pro-tumorigenic effects of MDSCs are well understood. Whether MDSCs are involved in promoting cancer cachexia is not well understood. We orthotopically injected the pancreas of mice with KPC cells or PBS. One group of tumor-bearing mice was treated with an anti-Ly6G antibody that depletes granulocytic MDSCs and neutrophils; the other received a control antibody. Anti-Ly6G treatment delayed body mass loss, reduced tibialis anterior (TA) muscle wasting, abolished TA muscle fiber atrophy, reduced diaphragm muscle fiber atrophy of type IIb and IIx fibers, and reduced atrophic gene expression in the TA muscles. Anti-ly6G treatment resulted in greater than 50% Ly6G+ cell depletion efficiency in the tumors and TA muscles. These data show that, in the orthotopic KPC model, anti-Ly6G treatment reduces the number of Ly6G+ cells in the tumor and skeletal muscle and reduces skeletal muscle atrophy. These data implicate Ly6G+ cells, including granulocytic MDSCs and neutrophils, as possible contributors to the development of pancreatic cancer-induced skeletal muscle wasting

Supplemental Protein during Heavy Cycling Training and Recovery Impacts Skeletal Muscle and Heart Rate Responses but Not Performance

The effects of protein supplementation on cycling performance, skeletal muscle function, and heart rate responses to exercise were examined following intensified (ICT) and reduced-volume training (RVT). Seven cyclists performed consecutive periods of normal training (NT), ICT (10 days; average training duration 220% of NT), and RVT (10 days; training duration 66% of NT). In a crossover design, subjects consumed supplemental carbohydrate (CHO) or an equal amount of carbohydrate with added protein (CP) during and following each exercise session (CP = +0.94 g/kg/day protein during ICT; +0.39 g/kg/day during RVT). A 30-kilometer time trial performance (following 120 min at 50% Wmax) was modestly impaired following ICT (+2.4 ± 6.4% versus NT) and returned to baseline levels following RVT (−0.7 ± 4.5% versus NT), with similar responses between CHO and CP. Skeletal muscle torque at 120 deg/s benefited from CP, compared to CHO, following ICT. However, this effect was no longer present at RVT. Following ICT, muscle fiber cross-sectional area was increased with CP, while there were no clear changes with CHO. Reductions in constant-load heart rates (at 50% Wmax) following RVT were likely greater with CP than CHO (−9 ± 9 bpm). Overall it appears that CP supplementation impacted skeletal muscle and heart rate responses during a period of heavy training and recovery, but this did not result in meaningful changes in time trial performance

Carbohydrate Mouth Rinsing Enhances High Intensity Time Trial Performance Following Prolonged Cycling

There is good evidence that mouth rinsing with carbohydrate (CHO) solutions can enhance endurance performance (≥30 min). The impact of a CHO mouth rinse on sprint performance has been less consistent, suggesting that CHO may confer benefits in conditions of ‘metabolic strain’. To test this hypothesis, the current study examined the impact of late-exercise mouth rinsing on sprint performance. Secondly, we investigated the effects of a protein mouth rinse (PRO) on performance. Eight trained male cyclists participated in three trials consisting of 120 min of constant-load cycling (55% Wmax) followed by a 30 km computer-simulated time trial, during which only water was provided. Following 15 min of muscle function assessment, 10 min of constant-load cycling (3 min at 35% Wmax, 7 min at 55% Wmax) was performed. This was immediately followed by a 2 km time trial. Subjects rinsed with 25 mL of CHO, PRO, or placebo (PLA) at min 5:00 and 14:30 of the 15 min muscle function phase, and min 8:00 of the 10-min constant-load cycling. Magnitude-based inferential statistics were used to analyze the effects of the mouth rinse on 2-km time trial performance and the following physiological parameters: Maximum Voluntary Contract (MVC), Rating of Perceived Exertion (RPE), Heart Rate (HR), and blood glucose levels. The primary finding was that CHO ‘likely’ enhanced performance vs. PLA (3.8%), whereas differences between PRO and PLA were unclear (0.4%). These data demonstrate that late-race performance is enhanced by a CHO rinse, but not PRO, under challenging metabolic conditions. More data should be acquired before this strategy is recommended for the later stages of cycling competition under more practical conditions, such as when carbohydrates are supplemented throughout the preceding minutes/hours of exercise

IL-8 Released from Human Pancreatic Cancer and Tumor-Associated Stromal Cells Signals through a CXCR2-ERK1/2 Axis to Induce Muscle Atrophy

Tumor-derived cytokines are known to drive the catabolism of host tissues, including skeletal muscle. However, our understanding of the specific cytokines that initiate this process remains incomplete. In the current study, we conducted multiplex analyte profiling of cytokines in conditioned medium (CM) collected from human pancreatic cancer (PC) cells, human tumor-associated stromal (TAS) cells, and their co-culture. Of the factors identified, interleukin-8 (IL-8) is released at high levels from PC cells and PC/TAS co-culture and has previously been associated with low muscle mass in cancer patients. We, therefore, treated C2C12 myotubes with IL-8 which led to the activation of ERK1/2, STAT, and Smad signaling, and induced myotube atrophy. Moreover, the treatment of mice with IL-8 also induced significant muscle wasting, confirming the in vivo relevance of IL-8 on muscle. Mechanistically, IL-8-induced myotube atrophy is inhibited by treatment with the CXCR2 antagonist, SB225002, or by treatment with the ERK1/2 inhibitor, U0126. We further demonstrate that this axis mediates muscle atrophy induced by pancreatic cancer cell CM, as neutralization of IL-8 or treatment with SB225002 or U0126 significantly inhibit CM-induced myotube atrophy. Thus, these data support a key role of IL-8 released from human PC cells in initiating atrophy of muscle cells via CXCR2-ERK1/2