Abstract
Although there is good evidence to indicate a major role of intrinsic impairment of the contractile apparatus in muscle weakness seen in several pathophysiological conditions, the factors responsible for control of myofibrillar function are not fully understood. To investigate the role of mechanical load in myofibrillar function, we compared the skinned fiber force between denervated (DEN) and dexamethasone-treated (DEX) rat skeletal muscles with or without neuromuscular electrical stimulation (ES) training. DEN and DEX were induced by cutting the sciatic nerve and daily injection of dexamethasone (5 mg/kg/day) for 7 days, respectively. For ES training, plantarflexor muscles were electrically stimulated to produce four sets of five isometric contractions each day. In situ maximum torque was markedly depressed in the DEN muscles compared to the DEX muscles (-74% vs. -10%), whereas there was not much difference in the degree of atrophy in gastrocnemius muscles between DEN and DEX groups (-24% vs. -17%). Similar results were obtained in the skinned fiber preparation, with a greater reduction in maximum Ca2+-activated force in the DEN than in the DEX group (-53% vs. -16%). Moreover, there was a parallel decline in myosin heavy chain (MyHC) and actin content per muscle volume in DEN muscles, but not in DEX muscles, which was associated with upregulation of NADPH oxidase (NOX) 2, neuronal nitric oxide synthase (nNOS), and endothelial NOS expression, translocation of nNOS from the membrane to the cytosol, and augmentation of mRNA levels of muscle RING finger protein 1 (MuRF-1) and atrogin-1. Importantly, mechanical load evoked by ES protects against DEN- and DEX-induced myofibrillar dysfunction and these molecular alterations. Our findings provide novel insights regarding the difference in intrinsic contractile properties between DEN and DEX and suggest an important role of mechanical load in preserving myofibrillar function in skeletal muscle.
Highlights
There is a growing body of evidence showing that loss of muscle strength results from muscle atrophy and from reductions in specific force in a variety of pathophysiological conditions [1, 2]
Images of membrane were collected following exposure to chemiluminescence substrate (Millipore) using a charge-coupled device camera attached to ChemiDOC MP (BioRad), and Image Lab Software was used for detection as well as densitometry
In order to clarify the mechanism underlying these differences, we assessed the myofibrillar function in skinned fibers and found that the magnitude of reduction in Pmax was obviously higher in DEN than in DEX group (-53% vs. -16%)
Summary
There is a growing body of evidence showing that loss of muscle strength results from muscle atrophy and from reductions in specific force (i.e. force per cross-sectional area) in a variety of pathophysiological conditions [1, 2]. Impaired membrane excitability and sarcoplasmic reticulum Ca2+ release may contribute to the reduction in specific force, studies using skinned fiber preparations have shown a significant decrease in maximum Ca2+-activated specific force (Pmax) in all fiber types following DEN [7, 8], suggesting a major role of intrinsic impairment of the contractile apparatus. It has been reported that a depletion of MuRF-1 spares muscle mass in DEN mice [14], but not in DEX mice [13]. These findings suggest that there are apparently distinct mechanisms between DEN- and DEXinduced muscle atrophy, and that the degradation of muscle proteins other than motor proteins may largely account for the muscle atrophy induced by DEX treatment
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
