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Background  Fukutin-related protein (FKRP) mutations are the most common cause of dystroglycanopathies known to cause both limb girdle and congenital muscular dystrophy. The  P448Lneo−  mouse model has a knock-in mutation in the FKRP gene and develops skeletal, respiratory, and cardiac muscle disease.    Methods  We studied the natural history of the  P448Lneo−  mouse model over 9 months and the effects of twice weekly treadmill running. Forelimb and hindlimb grip strength (Columbus Instruments) and overall activity (Omnitech Electronics) assessed skeletal muscle function. Echocardiography was performed using VisualSonics Vevo 770 (FujiFilm VisualSonics). Plethysmography was performed using whole body system (ADInstruments). Histological evaluations included quantification of inflammation, fibrosis, central nucleation, and fiber size variation.    Results   P448Lneo−  mice had significantly increased normalized tissue weights compared to controls at 9 months of age for the heart, gastrocnemius, soleus, tibialis anterior, quadriceps, and triceps. There were no significant differences seen in forelimb or hindlimb grip strength or activity monitoring in  P448Lneo−  mice with or without exercise compared to controls. Skeletal muscles demonstrated increased inflammation, fibrosis, central nucleation, and variation in fiber size compared to controls ( p  < 0.05) and worsened with exercise. Plethysmography showed significant differences in respiratory rates and decreased tidal and minute volumes in  P448Lneo−  mice ( p  < 0.01). There was increased fibrosis in the diaphragm compared to controls ( p  < 0.01). Echocardiography demonstrated decreased systolic function in 9-month-old mutant mice ( p  < 0.01). There was increased myocardial wall thickness and mass ( p  < 0.001) with increased fibrosis in 9-month-old  P448Lneo−  mice compared to controls ( p  < 0.05). mRNA expression for natriuretic peptide type A (Nppa) was significantly increased in  P448Lneo−  mice compared to controls at 6 months ( p  < 0.05) and for natriuretic peptide type B (Nppb) at 6 and 9 months of age ( p  < 0.05).    Conclusions  FKRP-deficient  P448Lneo−  mice demonstrate significant deficits in cardiac and respiratory functions compared to control mice, and this is associated with increased inflammation and fibrosis. This study provides new functional outcome measures for preclinical trials of FKRP-related muscular dystrophies.    Electronic supplementary material  The online version of this article (10.1186/s13395-018-0158-x) contains supplementary material, which is available to authorized users.

Skeletal, cardiac, and respiratory muscle function and histopathology in the P448Lneo− mouse model of FKRP-deficient muscular dystrophy