Early Markers of Cardiac and Skeletal Muscle Metabolic Derangement in the Apc(min/+) Male Mouse

Cancer cachexia is a metabolic and wasting disease that occurs in up to 80% of cancer patients. Currently, there are no clear diagnostic criteria, its effects are irreversible, and it cannot be treated. Most patients progress undetected to late stages of cancer cachexia, stop responding to traditional treatment, and die without an effective intervention. While the literature has begun to characterize late (refractory) cachexia muscle metabolic changes, less is known about early changes that may precede obvious muscle dysfunction and wasting. Therefore, this investigation aimed to characterize early phase heart and skeletal muscle metabolic changes in a preclinical model of colorectal cancer.

The Apc(min/+) mouse spontaneously forms tumors along the intestinal tract and is a well-accepted preclinical colorectal cancer model. To identify early changes in muscle metabolism during colorectal cancer development, heart and gastrocnemius tissues from 15-week-old male Apc(min/+) and litter-matched non-carrier mice (wildtype) were analyzed by untargeted GC/MS metabolomics.

In the heart, metabolic pathways related to taurine/hypotaurine metabolism; biosynthesis of unsaturated fatty acids; alanine, glutamate, and aspartate; arginine and proline; and arginine biosynthesis were affected by colorectal cancer. In skeletal muscle, metabolic pathways involving arginine biosynthesis; alanine, glutamate, aspartate, and proline metabolism were affected by cancer cachexia. Taken together, these data demonstrate altered arginine metabolism and proline metabolism in hearts and skeletal muscle of cachectic mice. Interestingly, cardiac muscle showed a non-preferential fuel switch towards less energetically favorable glycolysis (vs. fatty acid metabolism) that coincided with cardiac dysfunction, while skeletal muscle exhibited glucose dysregulation and possible insulin resistance.

These data characterize early cardiac and skeletal muscle metabolic derangements that lead to muscle dysfunction and atrophy during colorectal cancer. Such data could help identify patients in early phases of cachexia or identification of cardiac and skeletal muscle specific therapeutic targets aimed at early intervention.