Effects of a High-Protein Diet Combined with Pentoxifylline on Preventing Cachexia Associated with B16F10 Melanoma in Mice

• Grant number: 25/05046-6
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: July 01, 2025
• End date: December 31, 2028
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Isis Do Carmo Kettelhut
• Grantee: João Batista Camargo Neto
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Cachexia is a multifactorial syndrome characterized by skeletal muscle loss, affecting approximately 50% of cancer patients. Attenuating tumor growth can partially reverse muscle atrophy associated with cancer. In this context, previous studies have shown that a high-protein (HP) diet reduces tumor growth and metastasis. However, the impact of a HP diet on muscle mass and function in tumor cachexia and the underlying molecular mechanisms remain to be elucidated. Additionally, activation of the cAMP/PKA pathway in skeletal muscle has been implicated in mitigating tumor-induced muscle atrophy. While pentoxifylline (PTX) increases intramuscular cAMP levels and reduces muscle loss in cachectic animals, the molecular mechanisms underlying this effect remain unclear. Moreover, the efficacy of PTX as a monotherapy for preventing muscle deterioration in cachexia is uncertain. In this way, this study aims to determine whether metabolic adaptations induced by an HP diet, combined with cAMP/PKA pathway activation by PTX, can attenuate the loss of mass and function of skeletal muscle in tumor cachexia. To do that, C57/Bl6J (~8 weeks old) mice will be fed either a control or HP diet for 30 days, followed by inoculation with B16F10 cells (5×10¿) and treatment with PTX (100 mg/kg) for 25 days. In skeletal muscle, we will assess protein synthesis and degradation, contractile function, fiber phenotype, and key molecular regulators of muscle mass. The role of mTORC1 will be evaluated through in vivo rapamycin treatment, while PKA function will be examined via in vivo electroporation of a PKA inhibitory peptide. By investigating the impact of a HP diet and PTX on muscle mass and function in tumor cachexia, this study could uncover novel molecular mechanisms and identify potential therapeutic targets for managing cancer-related muscle wasting. (AU)