Cancer cachexia (CC) results in impaired muscle function and quality of life and is the primary cause of death for ~20-30% of cancer patients. We demonstrated mitochondrial degeneration as a precursor to CC in male mice, however, if such alterations occur in females is currently unknown. The purpose of this study was to elucidate muscle alterations in CC development in female tumor-bearing mice. 60 female C57BL/6J mice were injected with PBS or Lewis Lung Carcinoma at 8-week age, and tumors developed for 1, 2, 3, or 4 weeks to assess the time course of cachectic development. In vivo muscle contractile function, protein fractional synthetic rate (FSR), protein turnover, and mitochondrial health were assessed. 3- and 4-week tumor-bearing mice displayed a dichotomy in tumor growth and were reassigned to High Tumor (HT) and Low Tumor (LT) groups. HT mice exhibited lower soleus, TA, and fat weights compared to PBS. HT mice showed lower peak isometric torque and slower one-half relaxation time compared to PBS. HT mice had lower FSR compared to PBS while E3 ubiquitin ligases were greater in HT compared to other groups. Bnip3 (mitophagy) and pMitoTimer red puncta (mitochondrial degeneration) were greater in HT while Pgc1α1 and Tfam (mitochondrial biogenesis) were lower in HT compared to PBS. We demonstrate alterations in female tumor-bearing mice where HT exhibited greater protein degradation, impaired muscle contractility, and mitochondrial degeneration compared to other groups. Our data provide novel evidence for a distinct cachectic development in tumor-bearing female mice compared to previous male studies.

Background Muscle atrophy is a common pathology associated with disuse, such as prolonged bed rest or spaceflight, and is associated with detrimental health outcomes. There is emerging evidence that disuse atrophy may differentially affect males and females. Cellular mechanisms contributing to the development and progression of disuse remain elusive, particularly protein turnover cascades. The purpose of this study was to investigate the initial development and progression of disuse muscle atrophy in male and female mice using the well‐established model of hindlimb unloading (HU). Methods One hundred C57BL/6J mice (50 male and 50 female) were hindlimb suspended for 0 (control), 24, 48, 72, or 168 h to induce disuse atrophy (10 animals per group). At designated time points, animals were euthanized, and tissues (extensor digitorum longus, gastrocnemius, and soleus for mRNA analysis, gastrocnemius and extensor digitorum longus for protein synthesis rates, and tibialis anterior for histology) were collected for analysis of protein turnover mechanisms (protein anabolism and catabolism). Results Both males and females lost ~30% of tibialis anterior cross‐sectional area after 168 h of disuse. Males had no statistical difference in MHCIIB fibre area, whereas unloaded females had ~33% lower MHCIIB cross‐sectional area by 168 h of unloading. Both males and females had lower fractional protein synthesis rates (FSRs) within 24–48 h of HU, and females appeared to have a greater reduction compared with males within 24 h of HU (~23% lower FSRs in males vs. 40% lower FSRs in females). Males and females exhibited differential patterns and responses in multiple markers of protein anabolism, catabolism, and myogenic capacity during the development and progression of disuse atrophy. Specifically, females had greater mRNA inductions of catabolic factors Ubc and Gadd45a (~4‐fold greater content in females compared with ~2‐fold greater content in males) and greater inductions of anabolic inhibitors Redd1 and Deptor with disuse across multiple muscle tissues exhibiting different fibre phenotypes. Conclusions These results suggest that the aetiology of disuse muscle atrophy is more complicated and nuanced than previously thought, with different responses based on muscle phenotypes and between males and females, with females having greater inductions of atrophic markers early in the development of disuse atrophy.

microRNAs (miRs) are linked to various human diseases including Type 2 Diabetes Mellitus (T2DM) and emerging evidence suggests miRs may serve as potential therapeutic targets. Lower miR-16 content is consistent across different models of T2DM; however, the role of miR-16 in muscle metabolic health is still elusive. Therefore, the purpose of this study was to investigate how deletion of miR-16 in mice affects skeletal muscle metabolic health and contractile function in both sexes. This study was conducted using both in vitro (1) and in vivo (2) experiments. (1) We utilized C2C12 myoblasts to test if inhibition or overexpression of miR-16 affected insulin-mediated glucose handling. (2) We generated muscle-specific miR-16 knockout (KO) mice fed a high-fat diet (HFD) to assess how miR-16 content impacts metabolic and contractile properties including glucose tolerance, insulin sensitivity, muscle contractile function, protein anabolism, and mitochondrial network health. (1) Although inhibition of miR-16 induced impaired insulin signaling (p=0.002) and glucose uptake (p=0.014), overexpression of miR-16 did not attenuate lipid overload-induced insulin resistance using the diacylglycerol analog 1‐oleoyl‐2‐acetyl‐sn‐glycerol. (2) miR-16 deletion induced both impaired muscle contractility (p=0.031-0.033), and mitochondrial network health (p=0.008-0.018) in both sexes. However, while males specifically exhibited impaired insulin sensitivity following miR-16 deletion (p=0.030), female KO mice showed pronounced glucose intolerance (p=0.046), corresponding with lower muscle weights (p=0.015), and protein hyperanabolism (p=0.023). Our findings suggest distinct sex differences in muscle adaptation in response to miR-16 deletion and miR-16 may serve as a key regulator for metabolic dysregulation in T2DM.

No abstract

Summary: There is strong evidence that physical activity has a profound protective effect against multiple types of cancer. Here, we show that this effect may be mediated by factors released from skeletal muscle during simulated exercise, in situ, which suppress canonical anabolic signaling in breast cancer. We report attenuated growth of MCF7 breast cancer cells in the presence of a rodent-derived exercise conditioned perfusate, independent of prior exercise training. This reduction was concomitant with increased levels of DEPTOR protein and reduced mTOR activity.