One possible source of the stress can be linked to a weakened Rebamipide diaphragm muscle. Diaphragm muscles from dt mice generate less force, fatigue quicker and are more susceptible to mechanicallyinduced stress compared to wt diaphragm muscles. Given the importance of this muscle in breathing, a compromised diaphragm muscle in dt mice could result in inefficient oxygen intake leading to compensatory mechanisms from the cardiovascular system to maintain suitable oxygen saturation levels. It is unlikely that premature death of dt mice can be attributed to an intrinsic cardiomyopathy because this investigation revealed that dt hearts do not display overt signs of morphological or histological cardiac defects. Furthermore, according to the immunofluorescence experiments, the distribution of the primary cytoskeletal networks remains relatively intact when dystonin is absent. A plausible reason for the premature death of the dt mice could therefore be related to a compromised diaphragm muscle that would hinder the breathing capacities of dt mice. It is not known if the lack of one dystonin isoform in particular is responsible for the dt condition or if the absence of multiple isoforms is the underlying cause. Determination of the dystonin variant that is responsible for the disease may help us identify the precise cause of death in these mice. Rescue studies as well as tissue and isoform specific conditional knock-out experiments like the ones performed for plectin isoforms have been proposed to investigate Spirodiclofen whether one or multiple isoforms are responsible for the dt disorder. Additional studies targeting specific tissues, such as muscle, in which dystonin is expressed, are needed to further elucidate the underlying pathophysiology of the dt disease. For instance, cardiac muscle-specific dystonin knockout mice would be useful to investigate whether they would develop overt morphological defects of the heart with age or whether the absence of dystonin correlates with compromised exercise capacity.In summary, we reveal that dystonin-b isoforms localize at the Zdisc, within the H zone and the sarcolemma of cardiomyocytes as well at intercalated discs of cardiac tissue. Our results show that dystonindeficiency does not lead to overt cardiac defects at least in young mice.