Karjalainen, K. | Search bioRxiv

bioRxiv2024

Repression of the Wnt pathway effector TCF7L2 reverses lethal cachexia in mice with intestinal cancers

Hyper-activation of the canonical Wnt signaling pathway drives small intestine and colon tumors. As the major Wnt pathway effector in healthy intestines, TCF7L2 is a suspected oncogene in both cancer types. However, this has been challenging to verify because Tcf7l2 knockout is lethal. To circumvent lethality, we generated a novel transgenic mouse that allows dose-dependent, systemic, inducible and reversible repression of endogenous Tcf7l2 expression. Using this mouse, we demonstrate that TCF7L2 is essential for early adenoma development in the small intestine (ApcMin/+ mouse model) but not colon (DSS-treated ApcMin/+ mouse model). Once established however, neither small intestine nor colon adenomas require TCF7L2 for maintenance. Despite this, Tcf7l2 repression rescues both types of cancer mice from lethal cachexia--a prevalent cancer comorbidity characterized by debilitating weight loss and skeletal muscle atrophy. In colon cancer cachexia, elevated TCF7L2 in the gastrocnemius muscle induces atrophy by activating the transcription of multiple atrophy genes within the ubiquitin-proteasome and autophagy-lysosome systems. Hence, repressing Tcf7l2 normalizes atrophy gene expression back to non-cachectic expression levels and restores muscle mass. The cachexia recovery mechanism in small intestine cancer remains undefined but is independent of the gastrocnemius. This study shows that systemic and partial Tcf7l2 repression is both well-tolerated and effective in rescuing moribund cancer mice from cachexia-induced death. Hence this is a promising treatment strategy for cancer patients suffering from cachexia. Additionally, our transgenic mouse is a valuable tool to study muscle atrophy across other conditions including aging, diabetes and neuromuscular disease.

cancer biology↗

bioRxiv2021

A musculoskeletal finite element model of rat knee joint for evaluating cartilage biomechanics during gait

Abnormal loading of the knee due to injuries or obesity is thought to contribute to the development of osteoarthritis (OA). Small animal models have been used for studying OA progression mechanisms. However, numerical models to study cartilage responses under dynamic loading in preclinical animal models have not been developed. Here we present a musculoskeletal finite element (FE) model of a rat knee joint to evaluate cartilage biomechanical responses during a gait cycle. The rat knee joint geometries were obtained from a 3-D MRI dataset and the boundary conditions regarding loading in the joint were extracted from a musculoskeletal model of the rat hindlimb. The fibril-reinforced poroelastic (FRPE) properties of the rat cartilage were derived from data of mechanical indentation tests. Our numerical results showed the relevance of simulating anatomical and locomotion characteristics in the rat knee joint for estimating tissue responses such as contact pressures, stresses, strains, and fluid pressures. We found that the contact pressure and maximum principal strain were virtually constant in the medial compartment whereas they showed the highest values at the beginning of the gait cycle in the lateral compartment. Furthermore, we found that the maximum principal stress increased during the stance phase of gait, with the greatest values at midstance. We anticipate that our approach serves as a first step towards investigating the effects of gait abnormalities on the adaptation and degeneration of rat knee joint tissues and could be used to evaluate biomechanically-driven mechanisms of the progression of OA as a consequence of joint injury or obesity. Author SummaryOsteoarthritis is a disease of the musculoskeletal system which is characterized by the degradation of articular cartilage. Changes in the knee loading after injuries or obesity contribute to the development of cartilage degeneration. Since injured cartilage cannot be reversed back to intact conditions, small animal models have been widely used for investigating osteoarthritis progression mechanisms. Moreover, experimental studies have been complemented with numerical models to overcome inherent limitations such as cost, difficulties to obtain accurate measures and replicate degenerative situations in the knee joint. However, computational models to study articular cartilage responses under dynamic loading in small animal models have not been developed. Thus, here we present a musculoskeletal finite element model of a rat knee joint to evaluate cartilage biomechanical responses during gait. Our computational model considers both the anatomical and locomotion characteristics of the rat knee joint for estimating mechanical responses in the articular cartilage. We suggest that our approach can be used to investigate tissue adaptations based on the mechanobiological responses of the cartilage to prevent the progression of osteoarthritis.

bioengineering↗