The absence of MuRF1 protects against Calpain1‐induced systolic dysfunction in vivo

Protein degradation to maintain the cardiac contractile machinery is essential to the ongoing performance required of the heart. Multiple enzyme systems have been implicated in this process, including the ubiquitin‐proteasome system and Calpain(Capn) enzymes. In the heart, Capn1 is the primary calcium‐activated cysteine protease that physiologically degrades protein aggregates and sarcomere proteins upon activation. Activation of Capn1 results from pathological injury or stress, such as ischemia reperfusion injury and cardiac hypertrophy/heart failure. Recent evidence supports Capn1 involvement in regulating ubiquitination and subsequent degradation of sarcomeric proteins by an unidentified ubiquitin ligase. Muscle RING‐finger protein‐1(MuRF1) is an ubiquitin ligase expressed in striated muscle with many of the same muscle‐specific substrates as Capn1 (eg. troponin I). We hypothesized both Capn1 and MuRF1 are required for the pathological phenotypes associated with increased Capn1 activity. To test this, we crossed α‐MHC Capn1 transgenic mice (Capn1 Tg+) with MuRF1‐/‐ mice and followed their cardiac phenotype by conscious echocardiography. At 6 months, the Capn1 Tg+//MuRF1+/+ mice exhibited a significant reduction in fractional shortening associated with systolic dysfunction; in contrast, sibling Capn1 Tg+//MuRF1‐/‐ mice were largely protected. Capn1Tg+//MuRF1‐/‐ mice also did not exhibit the increased βMHC and ANF mRNA observed in the Capn1Tg+//MuRF1+/+ mice, which supports the absence of MuRF1 protects against pathological hypertrophy. Taken together, these data support a mechanism by which Capn protease and Murf1 ubiquitin‐proteasome pathways work in concert to degrade cardiac proteins in Capn1‐induced heart failure.