Background: Cardiac failure is a primary cause of mortality in patients with Duchenne (DMD) or Becker (BMD) muscular dystrophy. DMD and BMD are caused by mutations in the X-linked DMD gene that affect the expression and/or function of the dystrophin protein in striated muscles. Dystrophin plays an important structural function in protecting the muscle cell membrane from the repeated mechanical stresses of contraction. However, dystrophins with deletions that do not disrupt its structural functions, delay but do not prevent cardiac disease. This suggests the existence of additional non-structural functions of dystrophin that remain to be elucidated in order to develop effective treatments for heart failure in DMD and BMD. Aims: To investigate signalling changes associated with disease in the dystrophin deficient heart that are not corrected by an internally deleted dystrophin with preserved structural function (ΔR4-R23/ΔCT micro-dystrophin (µDys)). Methods: Kinase arrays were performed on whole heart tissue lysates from wild-type mice, dystrophin deficient mdx 5cv mice and mdx 5cv mice expressing µDys. Signalling pathways disrupted in mdx 5cv mice compared to wildtype that were not normalised by micro-dystrophin were further investigated by Western blotting and immunofluorescence assays to validate the array results. Additionally, we also assessed proteins known to be disrupted in dystrophin deficient hearts and to play a role in maintaining the structural integrity of cardiomyocytes or in cardiac conduction. To quantify Western blots densitometric analyses were performed and data expressed as mean fold change (FC) ± standard deviation versus wildtype. All groups were N=5 and statistical assessment was performed using one-way ANOVA with Bonferroni post hoc test for multiple comparisons. All animal procedures were performed in accordance with the Guidance on the Operation of the Animals (Scientific Procedures) Act, 1986 (UK Home Office). Results: Our group have recently shown that expression of µDys fully prevents cardiomyocyte hypertrophy and collagen fibrosis developing in the heart, despite perturbation to ERK 1/2 signalling (Wang et al., 2021). Here, we show that upstream of ERK 1/2, MEK 1/2 was hypo-phosphorylated in mdx 5cv (0.15±0.08 FC P<0.01) and not corrected by uDys (0.21±0.31 FC P<0.01). Akt was also hypo-phosphorylated in mdx 5cv (0.49±0.21 FC P<0.05 and not corrected by uDys (0.45±0.26 FC P<0.05). Additionally, sarcomeric protein α-actinin increased in abundance in mdx 5cv (2.90±0.48 FC P<0.01) but was normalised by uDys (1.52±1.25 FC N.S.). Finally, connexin 43, a key protein of intercalated disks that mediates cardiac conduction was mislocalised and over-abundant in mdx 5cv (3.19±1.05 FC P<0.01) and not normalised by uDys (2.27±0.57 FC P<0.05). Conclusions: In line with current understanding, our results confirm the ability of ΔR4-R23/ΔCT micro-dystrophin to restore the structural integrity of the dystrophin-deficient cardiomyocyte. However, key biochemical signalling pathways appear to remain perturbed and efforts to address such issues are required for fully effective therapies towards DMD and BMD.