Abstract
There is no cure or beneficial management option for Limb-Girdle muscular dystrophy (MD) type 2B (LGMD2B). Losartan, a blood pressure (BP) lowering angiotensin II (AngII) receptor type 1 (ATR1) blocker (ARB) with unique anti-transforming growth factor-β (TGF-β) properties, can protect muscles in various types of MD such as Duchenne MD, suggesting a potential benefit for LGMD2B patients. Herein, we show in a mild, dysferlin-null mouse model of LGMD2B that losartan increased quadriceps muscle fibrosis (142%; P<0.0001). In a severe, atherogenic diet-fed model of LGMD2B recently described by our group, losartan further exacerbated dysferlin-null mouse muscle wasting in quadriceps and triceps brachii, two muscles typically affected by LGMD2B, by 40% and 51%, respectively (P<0.05). Lower TGF-β signalling was not observed with losartan, therefore plasma levels of atherogenic lipids known to aggravate LGMD2B severity were investigated. We report that losartan increased both plasma triglycerides and cholesterol concentrations in dysferlin-null mice. Other protective properties of losartan, such as increased nitric oxide release and BP lowering, were also reduced in the absence of dysferlin expression. Our data suggest that LGMD2B patients may show some resistance to the primary BP-lowering effects of losartan along with accelerated muscle wasting and dyslipidemia. Hence, we urge caution on the use of ARBs in this population as their ATR1 pathway may be dysfunctional.
Highlights
Limb-girdle muscular dystrophy (MD) type 2B (LGMD2B) and Miyoshi myopathy are forms of MD caused by mutations in the dysferlin gene[1,2,3], a calcium-dependent sarcolemma repair and vesicle trafficking protein [[4,5] and reviewed in [6]]
The current study provides evidence in a preclinical model of dysferlinopathy that losartan does not prevent, but rather exacerbates muscle wasting and damage, which is in stark contrast to its protective effects in other types of MD and muscle disease
Previous work by us and other groups have shown that losartan can ameliorate the manifestation of muscle disease in mouse models of Duchenne muscular dystrophy (DMD), α2 laminin-deficient congenital MD type 1A (MDC1A), Marfan syndrome and sarcopenia, likely by attenuating the pro-fibrotic action of transforming growth factor-β (TGF-β) signalling [10,13,16,30,31]
Summary
Limb-girdle muscular dystrophy (MD) type 2B (LGMD2B) and Miyoshi myopathy are forms of MD caused by mutations in the dysferlin gene[1,2,3], a calcium-dependent sarcolemma repair and vesicle trafficking protein [[4,5] and reviewed in [6]]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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