Abstract

BackgroundThe ability to assess skeletal muscle function and delineate regulatory mechanisms is essential to uncovering therapeutic approaches that preserve functional independence in a disease state. Skeletal muscle provides distinct experimental challenges due to inherent differences across muscle groups, including fiber type and size that may limit experimental approaches. The flexor digitorum brevis (FDB) possesses numerous properties that offer the investigator a high degree of experimental flexibility to address specific hypotheses. To date, surprisingly few studies have taken advantage of the FDB to investigate mechanisms regulating skeletal muscle function. The purpose of this study was to characterize and experimentally demonstrate the value of the FDB muscle for scientific investigations.MethodsFirst, we characterized the FDB phenotype and provide reference comparisons to skeletal muscles commonly used in the field. We developed approaches allowing for experimental assessment of force production, in vitro and in vivo microscopy, and mitochondrial respiration to demonstrate the versatility of the FDB. As proof-of principle, we performed experiments to alter force production or mitochondrial respiration to validate the flexibility the FDB affords the investigator.ResultsThe FDB is made up of small predominantly type IIa and IIx fibers that collectively produce less peak isometric force than the extensor digitorum longus (EDL) or soleus muscles, but demonstrates a greater fatigue resistance than the EDL. Unlike the other muscles, inherent properties of the FDB muscle make it amenable to multiple in vitro- and in vivo-based microscopy methods. Due to its anatomical location, the FDB can be used in cardiotoxin-induced muscle injury protocols and is amenable to electroporation of cDNA with a high degree of efficiency allowing for an effective means of genetic manipulation. Using a novel approach, we also demonstrate methods for assessing mitochondrial respiration in the FDB, which are comparable to the commonly used gastrocnemius muscle. As proof of principle, short-term overexpression of Pgc1α in the FDB increased mitochondrial respiration rates.ConclusionThe results highlight the experimental flexibility afforded the investigator by using the FDB muscle to assess mechanisms that regulate skeletal muscle function.

Highlights

  • The ability to assess skeletal muscle function and delineate regulatory mechanisms is essential to uncovering therapeutic approaches that preserve functional independence in a disease state

  • We demonstrate the utility of the flexor digitorum brevis (FDB) as a model for assessing skeletal muscle function across a range of methodologies commonly used within the skeletal muscle research community, including isometric force production, in vitro and in vivo imaging, and mitochondrial respiration

  • In vitro and in vivo microscopy Here we demonstrate the FDB muscle is amenable to multiple imaging approaches

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Summary

Introduction

The ability to assess skeletal muscle function and delineate regulatory mechanisms is essential to uncovering therapeutic approaches that preserve functional independence in a disease state. Skeletal muscle is susceptible to a number of genetic, environmental, and age-related pathologies that impair the tissue’s normal mechanical and metabolic function. This often leads to the development of comorbidities and sometimes death. Muscles commonly used for functional and mechanistic experiments include the extensor digitorum longus (EDL), soleus, plantaris, gastrocnemius, tibialis anterior (TA), and/or the quadriceps. These muscles each offer unique advantages across a host of methodologies including measuring isometric force production, susceptibility to muscle injury, mitochondrial respiration, protein content, and histology.

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