Duchenne muscular dystrophy (DMD) is the most common childhood-onset muscle degenerative disease worldwide. DMD is caused by genetic deficiency of dystrophin resulting in loss of ambulation and premature death due to heart failure. Ongoing DMD gene therapy clinical trials delivering miniaturized dystrophin with adeno-associated virus (AAV) to replace dystrophin have inconclusive results. FDA-approved ELEVIDYS failed to meet Phase III primary endpoints to improve overall motor function. Pfizer’s DMD gene therapy clinical trial reported two treatment-related patient deaths, both presenting with cardiac involvement. Lastly, across all clinical trials, patients that experienced treatment-related serious adverse events showed strong T cell reactivity to dystrophin epitopes that mapped to their genetic deletion site, indicating the absence of central tolerance. Therefore, concerns remain regarding treatment efficacy and safety. Miniaturized utrophin (AAV-μUtro) is an attractive alternative that rescues skeletal muscle disease progression in the absence of immune responses to the transgene product. It remains untested whether AAV-μUtro is protective in the dystrophic heart, due to imperfect animal models of DMD cardiomyopathy. Here we developed a reproducible pharmacologic and exercise cardiac injury method in the DMD mdx mouse. AAV-μUtro was highly protective against cardiac injury, demonstrated by reduced biochemical and histological markers compared to untreated mdx mice. AAV-μUtro significantly improved exercise performance and prevented maladaptive cardiac remodeling in response to daily running. Protection against myocardial injury persisted at least 10 months post-treatment. Taken together, these results demonstrate long-term cardioprotection by AAV-μUtro against pharmacologic and exercise-induced cardiac stress. These results are promising for the longevity of clinical benefit during daily activity in children with Duchenne. One limitation across all first-generation DMD gene therapies is fragmentation of the protein products in vivo, raising concerns on whether the current design of miniaturized dystrophin-mimetics generates unstable products under mechanical loading, leading to loss of the protein and protection overtime. Here we leveraged the evolutionary history of the dystrophin gene in an innovative design of next-generation dystrophin-mimetics. We demonstrate that next-generation transgenes confer superior stability and cardioprotection in mdx mice compared to the first-generation FDA-approved AAV-micro-dystrophin.