Paraspinal Muscle Contractile Function is Impaired in the ENT1-deficient Mouse Model of Progressive Spine Pathology

Abstract

Study Design. Basic science study of the relationship between spine pathology and the contractile ability of the surrounding muscles.Objective. The aim of this study was to investigate single muscle fiber contractile function in a model of progressive spine mineralization (ENT1 À/À mice). Summary of Background Data. Altered muscle structure and function have been associated with various spine pathologies; however, studies to date have provided limited insight into the fundamental ability of spine muscles to actively contract and generate force, and how this may change in response to spine pathology. Methods. Experiments were performed on two groups (ENT1 À/ À [KO] and ENT1 þ/þ [WT]) of mice at 8 months of age (n ¼ 12 mice/group). Single muscle fibers were isolated from lumbar multifidus and erector spinae, as well as tibialis anterior (a non-spine-related control) and tested to determine their active contractile characteristics. Results. The multifidus demonstrated decreases in specific force (type IIax fibers: 36% decrease; type IIb fibers: 29% decrease), active modulus (type IIax: 35% decrease; type IIb: 30% decrease), and unloaded shortening velocity (V o ) (type IIax: 31% decrease) in the ENT1 À/À group when compared to WT controls. The erector spinae specific force was reduced in the ENT1 À/À mice when compared to WT (type IIax: 29% decrease), but active modulus and V o were unchanged. There were no differences in any of the active contractile properties of the lower limb TA muscle, validating that impairments observed in the spine muscles were specific to the underlying spine pathology and not the global loss of ENT1. Conclusion. These results provide the first direct evidence of cellular level impairments in the active contractile force generating properties of spine muscles in response to chronic spine pathology.

Paraspinal muscle pathophysiology associated with low back pain and spine degenerative disorders

“…Recently, the paraspinal muscles from these ENT1 −/− (KO) mice have also been shown to have impaired active contractile function. 120 Particularly, specific force (maximal isometric force normalized to CSA), unloaded shortening velocity (proxy for contractile speed of cross‐bridge interactions) and active modulus (proxy for number of attached cross‐bridges normalized to CSA) were all lower in the multifidus of the ENT1 −/− (KO) compared to the WT mice. Meanwhile, only the specific force was lower in the erector spinae KO group when compared to WT controls.…”

“…Interestingly, the reduced multifidus and erector spinae stiffness was apparent only within individual muscle fibers and not bundles of fibers, suggesting that remodeling was limited to the muscle cells themselves and not their connective tissue extracellular matrix. Recently, the paraspinal muscles from these ENT1 −/− (KO) mice have also been shown to have impaired active contractile function 120 . Particularly, specific force (maximal isometric force normalized to CSA), unloaded shortening velocity (proxy for contractile speed of cross‐bridge interactions) and active modulus (proxy for number of attached cross‐bridges normalized to CSA) were all lower in the multifidus of the ENT1 −/− (KO) compared to the WT mice.…”

“…Due to the many challenges in conducting studies on human LBPD patients (e.g., accessing healthy and pathological spine muscle tissue and conducting longitudinal studies probing cause‐and‐effect), animal experiments can provide a means to study mechanistic cause‐effect relationships between muscle and spine degeneration/dysfunction. Each of experimental (for example, References 111 , 112 , 113 , 114 , 115 ), naturally developing 116 and genetically induced (for example, 117 , 118 , 119 , 120 ) animal models have been utilized to answer important fundamental and clinical questions. As such, the following section will be divided into animal models that are (a) experimentally (surgically) induced and (b) naturally occurring and genetically induced.…”

“…The disadvantage of experimental animal models of spine pathology is that they require an overt injury to initiate the progressive degenerative changes; a sequence which may not mimic the naturally developing process in humans. Therefore, naturally occurring or genetically induced spine pathology models in dogs 116 and mice, 117 , 118 , 119 , 120 respectively, have also been used, which may provide additional insight into how pathological changes to the spine interact with the surrounding muscles in a more progressively developing manner.…”

Biomechanical Properties of Paraspinal Muscles Influence Spinal Loading—A Musculoskeletal Simulation Study

“…Even in these models, most of the required muscle parameters are either assumed or taken from cadaveric studies. For example, the passive elastic modulus, slack sarcomere length, and specific tension are assumed to be the same for all muscles in these models, while those have been shown to differ between muscle groups or between pathologies ( Ward et al, 2009c ; Lieber et al, 2003 ; Smith et al, 2011 ; Luden et al, 2008 ; Noonan et al, 2021 ). Due to the ethical and technical challenges, only a few and limited in vivo measurements of these parameters have been made to date ( Ward et al, 2009c ; Malakoutian, 2021 ).…”