Quercetin Improved Muscle Mass and Mitochondrial Content in a Murine Model of Cancer and Chemotherapy-Induced Cachexia

Abstract

A cachexia diagnosis is associated with a doubling in hospital stay and increased healthcare cost for cancer patients and most cachectic patients do not survive treatment. Unfortunately, complexity in treating cachexia is amplified by both the underlying malignancy and the anti-cancer therapy which can independently promote cachexia. Quercetin, an organic polyphenolic flavonoid, has demonstrated anti-inflammatory and antioxidant properties with promise in protecting against cancer and chemotherapy-induced dysfunction; however, whether quercetin is efficacious in maintaining muscle mass in tumor-bearing animals receiving chemotherapy has not been investigated. C26 tumor-bearing mice were given 5-fluorouracil (5FU; 30 mg/kg of lean mass i.p.) concomitant with quercetin (Quer; 50 mg/kg of body weight via oral gavage) or vehicle. Both C26 + 5FU and C26 + 5FU + Quer had similar body weight loss; however, muscle mass and cross-sectional area was greater in C26 + 5FU + Quer compared to C26 + 5FU. Additionally, C26 + 5FU + Quer had a greater number and larger intermyofibrillar mitochondria with increased relative protein expression of mitochondrial complexes V, III, and II as well as cytochrome c expression. C26 + 5FU + Quer also had increased MFN1 and reduced FIS1 relative protein expression without apparent benefits to muscle inflammatory signaling. Our data suggest that quercetin protected against cancer and chemotherapy-induced muscle mass loss through improving mitochondrial homeostatic balance.

Obesity worsens mitochondrial quality control and does not protect against skeletal muscle wasting in murine cancer cachexia

“…Protein isolation and western blotting was completed similar to as previously described. 7,21 The left gastrocnemius muscle was excised, snap frozen in liquid nitrogen, and stored at À80°C. The gastrocnemius was homogenized and 10-50 μg of crude muscle protein homogenate was separated via SDS-PAGE and transferred to a PVDF membrane.…”

“…Skeletal muscle was prepared for TEM as described. 7,22 Left solei were excised from a randomly selected cohort of mice (n = 4/group) and initially fixed in 2.5% EM-grade glutaraldehyde followed by a secondary fixation in 1% osmium tetroxide and 1.5% K + ferricyanide. After dehydration with increasing concentrations of ethanol, the samples were transferred to acetonitrile and embedded in Polybed 812.…”

“…Slides were fixed in ice-cold acetone and H&E staining was completed as previously described. 7,25 Images of H&E stains were taken at 20× magnification using a Keyence BZX800 microscope. Muscle cross sectional area (mCSA) was assessed using imaging software (ImageJ, NIH) by measuring the circumference of 500-700 myofibres/mouse (n = 3-5/group).…”

“…3 While the aetiology of cachexia is diverse, disrupted mitochondrial homeostasis has been implicated in its progression. [4][5][6][7][8] At the time of diagnosis, 40-60% of cancer patients are overweight and/or obese. 9 Unfortunately, however, there is a dearth of literature on the impact of pre-existing obesity on cancer-induced functional decrements, muscle mass loss, or other cachexia indices (i.e., inflammation and mitochondrial dysfunction).…”

“…Cachexia is most prevalent in patients with pancreatic, lung, colorectal and gastrointestinal cancers 3 . While the aetiology of cachexia is diverse, disrupted mitochondrial homeostasis has been implicated in its progression 4–8 …”