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Muscle contraction induces osteogenic levels of cortical bone strain despite muscle weakness in a mouse model of Osteogenesis Imperfecta.

ABSTRACT: Mechanical interactions between muscle and bone have long been recognized as integral to bone integrity. However, few studies have directly measured these interactions within the context of musculoskeletal disease. In this study, the osteogenesis imperfecta murine model (oim/oim) was utilized because it has both reduced bone and muscle properties, allowing direct assessment of whether weakened muscle is able to engender strain on weakened bone. To do so, a strain gauge was attached to the tibia of healthy and oim/oim mice, muscles within the posterior quadrant of the lower hind limb were stimulated, and bone strain during muscle contraction was measured. Results indicated that the relationship between maximum muscle torque and maximum engendered strain is altered in oim/oim bone, with less torque required to engender strain compare to wild-type and heterozygous mice. Maximum muscle torque at 150 Hz stimulation frequency was able to engender ~1500 ?? in oim/oim animals. However, even though the strain engendered in the oim/oim mice was high relative to historical bone formation thresholds, the maximum strain values were still significantly lower than that of the wild-type mice. These results are promising in that they suggest that muscle stimulation may be a viable means of inducing bone formation in oim/oim and potentially other disease models where muscle weakness/atrophy exist.

SUBMITTER: Berman AG

PROVIDER: S-EPMC7720097 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Muscle contraction induces osteogenic levels of cortical bone strain despite muscle weakness in a mouse model of Osteogenesis Imperfecta.

Berman Alycia G AG Organ Jason M JM Allen Matthew R MR Wallace Joseph M JM

Bone 20191202

Mechanical interactions between muscle and bone have long been recognized as integral to bone integrity. However, few studies have directly measured these interactions within the context of musculoskeletal disease. In this study, the osteogenesis imperfecta murine model (oim/oim) was utilized because it has both reduced bone and muscle properties, allowing direct assessment of whether weakened muscle is able to engender strain on weakened bone. To do so, a strain gauge was attached to the tibia ...[more]

PMID: 31805389

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Project description:BackgroundWe have previously shown that the deletion of the superoxide scavenger, CuZn superoxide dismutase, in mice (Sod1-/- mice) results in increased oxidative stress and an accelerated loss of skeletal muscle mass and force that mirror the changes seen in old control mice. The goal of this study is to define the effect of oxidative stress and ageing on muscle weakness and the Excitation Contraction (EC) coupling machinery in age-matched adult (8-10 months) wild-type (WT) and Sod1-/- mice in comparison with old (25-28 months) WT mice.MethodsIn vitro contractile assays were used to measure muscle contractile parameters. The activity of the sarcoplasmic reticulum Ca2+ ATPase (SERCA) pump was measured using an NADH-linked enzyme assay. Immunoblotting and immunofluorescence techniques were used to measure protein expression, and real-time reverse transcription PCR was used to measure gene expression.ResultsThe specific force generated by the extensor digitorum longus muscle was reduced in the Sod1-/- and old WT mice compared with young WT mice along with significant prolongation of time to peak force, increased half relaxation time, and disruption of intracellular calcium handling. The maximal activity of the SERCA calcium uptake pump was significantly reduced in gastrocnemius muscle from both old WT (≈14%) and adult Sod1-/- (≈33%) mice compared with young WT mice along with increased expression of sarcolipin, a known inhibitor of SERCA activity. Protein levels of the voltage sensor and calcium uptake channel proteins dihydropyridine receptor α1 and SERCA2 were significantly elevated (≈45% and ≈57%, respectively), while the ratio of calstabin, a channel stabilizing protein, to ryanodine receptor was significantly reduced (≈21%) in Sod1-/- mice compared with young WT mice. The changes in calcium handling were accompanied by substantially elevated levels of global protein carbonylation and lipid peroxidation.ConclusionsOur data suggest that the muscle weakness in Sod1-/- and old WT mice is in part driven by reactive oxygen species-mediated EC uncoupling and supports a role for reduced SERCA pump activity in compromised muscle function. The novel quantitative mechanistic data provided here can lead to potential therapeutic interventions of SERCA dysfunction for sarcopenia and muscle diseases.

Dataset Information

Muscle contraction induces osteogenic levels of cortical bone strain despite muscle weakness in a mouse model of Osteogenesis Imperfecta.

Publications

Muscle contraction induces osteogenic levels of cortical bone strain despite muscle weakness in a mouse model of Osteogenesis Imperfecta.

Similar Datasets

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