Significance We have found that long telomeres protect mice from genetic cardiac diseases analogous to those found in humans, such as Duchenne muscular dystrophy (DMD). Mice lacking dystrophin, similar to patients with DMD, exhibit only mild disease. In contrast, mice that lack dystrophin and have “humanized” telomere lengths ( mdx ^4cv /mTR ^G2 ) fully manifest both the severe human skeletal muscle wasting and cardiac failure typical of DMD. Remarkably, telomere shortening accompanies cardiac development even after cardiomyocyte division has ceased. This chronic proliferation-independent shortening in dystrophin-deficient cardiomyocytes is associated with induction of a DNA damage response, mitochondrial dysfunction, increased oxidative stress, and metabolic failure. Our findings highlight an interplay between telomere length and mitochondrial homeostasis in the etiology of dystrophic heart failure.