Diltiazem improves contractile properties of skeletal muscle in dysferlin-deficient BLAJ mice, but does not reduce contraction-induced muscle damage

Abstract

B6.A‐Dysf prmd/GeneJ (BLAJ) mice model human limb‐girdle muscular dystrophy 2B (LGMD2B), which is linked to mutations in the dysferlin (DYSF) gene. We tested the hypothesis that, the calcium ion (Ca2+) channel blocker diltiazem (DTZ), reduces contraction‐induced skeletal muscle damage, in BLAJ mice. We randomly assigned mice (N = 12; 3–4 month old males) to one of two groups – DTZ (N = 6) or vehicle (VEH, distilled water, N = 6). We conditioned mice with either DTZ or VEH for 1 week, after which, their tibialis anterior (TA) muscles were tested for contractile torque and susceptibility to injury from forced eccentric contractions. We continued dosing with DTZ or VEH for 3 days following eccentric contractions, and then studied torque recovery and muscle damage. We analyzed contractile torque before eccentric contractions, immediately after eccentric contractions, and at 3 days after eccentric contractions; and counted damaged fibers in the injured and uninjured TA muscles. We found that DTZ improved contractile torque before and immediately after forced eccentric contractions, but did not reduce delayed‐onset muscle damage that was observed at 3 days after eccentric contractions.

Angiotensin II receptor blocker losartan exacerbates muscle damage and exhibits weak blood pressure-lowering activity in a dysferlin-null model of Limb-Girdle muscular dystrophy type 2B

“…How blood pressure lowering medications impact both vascular and muscle tissue homeostasis in the LGMD2B patient population is poorly understood. Although, previous work has shown that Diltiazem, a Ca 2+ channel blocker with blood pressure lowering capabilities, can elicit partial protection in dysferlin-null tissues using acute damage models [54]. Our group has recently shown that losartan mediates its off-target, NO-protective effects on vascular tissues in a VEGFR-dependent manner [21]; a function shown to be ablated in dysferlin-deficient cells [55].…”

Damaged muscle fibers might masquerade as hybrid fibers – a cautionary note on immunophenotyping mouse muscle with mouse monoclonal antibodies

“…To demonstrate that damaged fibers label falsely as hybrid fibers, we followed a protocol of injurious eccentric contractions, which has been described in detail. 16 We exposed the left TA to 40 eccentric contractions (under general anesthesia; inhaled, 2-5% for induction and 1-4% for maintenance), performed in 4 sets of 10 repetitions, with 2 min rest between sets. For each eccentric contraction, the dorsiflexors were tetanically stimulated, and the foot was plantarflexed from 90 to 160°, at 300 /S.…”

“…For each eccentric contraction, the dorsiflexors were tetanically stimulated, and the foot was plantarflexed from 90 to 160°, at 300 /S. 16 The right TA served as an unexercised control.…”

The Dysferlinopathies Conundrum: Clinical Spectra, Disease Mechanism and Genetic Approaches for Treatments

“…Diltiazem, a calcium ion channel blocker, improves the contractile properties of skeletal muscle in BLA/J mice but does not appear to reduce contraction-induced muscle damage [191]. While it boosts muscle performance after eccentric contractions, it does not significantly reduce delayed-onset muscle damage.…”