Iron supplementation is sufficient to rescue skeletal muscle mass and function in cancer cachexia

• Published in: EMBO reports 2022-04, Vol.23 (4), p.e53746-n/a
• Main Authors: Wyart, Elisabeth, Hsu, Myriam Y, Sartori, Roberta, Mina, Erica, Rausch, Valentina, Pierobon, Elisa S, Mezzanotte, Mariarosa, Pezzini, Camilla, Bindels, Laure B, Lauria, Andrea, Penna, Fabio, Hirsch, Emilio, Martini, Miriam, Mazzone, Massimiliano, Roetto, Antonella, Geninatti Crich, Simonetta, Prenen, Hans, Sandri, Marco, Menga, Alessio, Porporato, Paolo E
• Format: Article
• Language: English
• Subjects: Animals; Atrophy; Availability; Cachexia; Cachexia - etiology; Cachexia - metabolism; Cancer; Chelating agents; Dietary Supplements; EMBO03; EMBO21; EMBO25; Energy metabolism; Humans; Iron; Iron - metabolism; Iron deficiency; Metabolism; Mice; Mitochondria; muscle; Muscle, Skeletal - metabolism; Muscles; Musculoskeletal system; Myotubes; Neoplasms - complications; Neoplasms - drug therapy; Neoplasms - metabolism; Nutrient deficiency; Oxidative metabolism; Patients; Skeletal muscle; Tumors
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.202153746

Cachexia is a wasting syndrome characterized by devastating skeletal muscle atrophy that dramatically increases mortality in various diseases, most notably in cancer patients with a penetrance of up to 80%. Knowledge regarding the mechanism of cancer‐induced cachexia remains very scarce, making cachexia an unmet medical need. In this study, we discovered strong alterations of iron metabolism in the skeletal muscle of both cancer patients and tumor‐bearing mice, characterized by decreased iron availability in mitochondria. We found that modulation of iron levels directly influences myotube size in vitro and muscle mass in otherwise healthy mice. Furthermore, iron supplementation was sufficient to preserve both muscle function and mass, prolong survival in tumor‐bearing mice, and even rescues strength in human subjects within an unexpectedly short time frame. Importantly, iron supplementation refuels mitochondrial oxidative metabolism and energy production. Overall, our findings provide new mechanistic insights in cancer‐induced skeletal muscle wasting, and support targeting iron metabolism as a potential therapeutic option for muscle wasting diseases. Synopsis Cancer induces striking alterations in iron metabolism of the skeletal muscle and iron supplementation prevents muscle atrophy and loss of strength. Cancer‐induced muscle atrophy features suppressed TFR1 expression and impaired iron sensing. Reduction of iron availability by means of chemical chelators, iron‐deficient diet, or genetic knockdown of TFR1 in vitro and/or in vivo is sufficient to trigger muscle atrophy. Replenishing mitochondrial iron rescues cancer‐induced metabolic dysfunction. Iron supplementation prevents muscle wasting in tumor‐bearing mice and improves cancer patient strength. Graphical Abstract Cancer induces striking alterations in iron metabolism of the skeletal muscle and iron supplementation prevents muscle atrophy and loss of strength.