Multiple Tripartite Motif E3 Ubiquitin Ligases Facilitate Skeletal Muscle Atrophy

Abstract

Muscle atrophy involves a loss of muscle mass and decreased contractile force production as part of the pathophysiology of many conditions including heart failure‐ or cancer‐induced cachexia, disuse atrophy, and age‐related sarcopenia. Decreased muscle fiber size and other mechanisms contribute to a loss of muscle strength resulting in frailty that compromises the health and well‐being of patients. During heart failure the degree of cachexia more closely correlates with fatigue level than the ejection fraction of the heart, and over 20% of cancer patients suffer diminished quality of life and eventually succumb to cachexia symptoms rather than as a direct result of the cancer itself. Atrophy requires ubiquitination of many muscle proteins through the action of E3 ubiquitin ligases. Two key E3 ligases, MURF1 and MAFbx/Atrogin‐1, are upregulated in several types of muscle atrophy and are essential for the atrophic response to occur during a variety of different stimulus. MURF1, also known as TRIM63, belongs to the large family of tripartite motif (TRIM) E3 ubiquitin ligases suggesting that other TRIM family members may have important roles during atrophy. Since many proteins in the muscle fiber must be ubiquitinated through targeting by specific E3 ligases, multiple novel E3 ligases must be required for muscle atrophy to occur. There are several candidate TRIM proteins that could potentially contribute to muscle atrophy. TRIM72/MG53 is on potential candidate E3 ligase as it is implicated in myoblast differentiation and muscle hypertrophy while its loss leads to susceptibility to cell membrane injury. However, little is known regarding the function of TRIM72 in muscle atrophy. Our current study investigates the role of TRIM72 in multiple models of muscle atrophy. Mouse models of cancer‐induced cachexia, dexamethasone induced muscle atrophy, and hind limb unloading were utilized in these experiments. Our findings show increased expression of TRIM72 protein in tibialis anterior and soleus muscles isolated from these mouse models of muscle atrophy. To evaluate the functional role of TRIM72 in skeletal muscle atrophy, muscles from trim72−/− and wild type mice following 12 days of hindlimb unloading were evaluated. Muscles from trim72−/−mice are resistant to disuse atrophy as these mice lost a lower percentage of muscle mass than wild type mice. Similarly, studies using dexamethasone to induce atrophy indicate decreased atrophy in trim72−/− muscles compared to wild type mice. These results establish that TRIM72 expression increases in parallel to other atrophy‐linked E3 ligases and that the expression of TRIM72 is necessary for the efficient atrophy of skeletal muscle following various muscle wasting stimuli. Targeting TRIM72 and other related E3 ubiquitin ligases could potentially act as a therapeutic approach for the treatment of different forms of muscle atrophy.