Reduced sucrose nonfermenting AMPK-related kinase (SNARK) activity aggravates cancer-induced skeletal muscle wasting

• Published in: Biomedicine & pharmacotherapy 2019-09, Vol.117, p.109197-109197, Article 109197
• Main Authors: Alves, Christiano R.R., MacDonald, Tara L., Nigro, Pasquale, Pathak, Prerana, Hirshman, Michael F., Goodyear, Laurie J., Lessard, Sarah J.
• Format: Article
• Language: English
• Subjects: Aging; AMP-Activated Protein Kinases - metabolism; AMPK; Animals; Apoptosis - physiology; Cachexia - metabolism; Cachexia - pathology; Cancer cachexia; Carcinoma, Lewis Lung - complications; Carcinoma, Lewis Lung - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle atrophy; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular Atrophy - etiology; Muscular Atrophy - metabolism; Muscular Atrophy - pathology; Protein-Serine-Threonine Kinases - metabolism; Sucrose - metabolism
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2019.109197

[Display omitted] •Lewis Lung Carcinoma regulates SNARK phosphorylation in skeletal muscle.•Muscle-specific SNARK-inactive transgenic mice are more susceptible to cachexia.•Lack of SNARK activity in skeletal muscle aggravates cancer-induced skeletal muscle wasting.•Lack of SNARK activity increases BAX protein expression, a marker of apoptosis. Sucrose nonfermenting AMPK-related kinase (SNARK) is a member of the AMPK family of kinases and has been implicated in the regulation of critical metabolic processes. Recent findings demonstrate that SNARK has an important role in the maintenance of muscle mass with age. Loss of skeletal muscle mass (cachexia) is a key problem for cancer patients. Thus, based on our previous findings with aging, we hypothesized that SNARK would play a role in regulating muscle mass under conditions of cancer cachexia. To test this hypothesis, Lewis Lung Carcinoma tumor cells or vehicle were injected subcutaneously in the right flank of wild type mice, muscle-specific transgenic mice expressing inactive SNARK mutant (SDN) or muscle-specific transgenic mice overexpressing wild-type SNARK (SWT). All tumor-bearing mice presented muscle wasting compared to vehicle-injected mice. However, SDN tumor-bearing mice had more pronounced atrophy compared to wild-type and SWT tumor-bearing mice. Histological analysis confirmed muscle atrophy in tumor-bearing mice, and SDN tumor-bearing mice exhibited a significantly smaller skeletal muscle cross-sectional area than wild-type and SWT tumor-bearing mice. Moreover, SDN tumor-bearing mice had increased skeletal muscle BAX protein expression, a marker of apoptosis, compared to other groups.Thus, lack of SNARK in skeletal muscle aggravates cancer-induced skeletal muscle wasting. These findings uncover a role for SNARK in the maintenance of skeletal muscle mass under cachexia conditions.