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Soft tissue manipulation enhances recovery of muscle mass in a disuse model of sarcopenia

De Gruyter
Journal of Osteopathic Medicine
Authors:
Basil Mustaklem
Basil Mustaklem
Basil Mustaklem
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Mary Terry Loghmani
Mary Terry Loghmani
Mary Terry Loghmani
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Abigail K Waterfill
Abigail K Waterfill
Abigail K Waterfill
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Mackenzie Caron
Mackenzie Caron
Mackenzie Caron
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Abstract

Context Sarcopenia is a disease characterized by low muscle mass and function that places individuals at greater risk of disability, loss of independence, and death. Current therapies include addressing underlying performance issues, resistance training, and/or nutritional strategies. However, these approaches have significant limitations, and chronic inflammation associated with sarcopenia may blunt the anabolic response to exercise and nutrition. This presents an unmet need for treatment strategies that promote gains in muscle function. One such possibility is soft tissue manipulation (STM), which is a noninvasive, nonpharmacological mechanotherapy employed by osteopathic physicians, physiotherapists, and massage therapists, wherein soft tissues are subjected to mechanical forces delivered by hand or by an instrument. However, the molecular effects of STM in sarcopenia remain largely unknown. Objectives In the present study, we utilized a rat model of sarcopenia due to disuse atrophy and examined the effects of STM on recovery of muscle mass and regulation of pro-/anti-inflammatory cytokines. Methods Ten-week-old male Brown Norway rats were subjected to 2-week hindlimb suspension (HLS) and then allowed to re-ambulate for 8 days with or without instrument-assisted soft tissue manipulation (IASTM) applied to the right hindlimb. Muscle weights were determined for treated and nontreated hindlimbs, and membrane-based cytokine arrays were performed on treated tissue and serum. Results Following suspension, IASTM enhanced the effectiveness of re-ambulation (Re-A) on muscle mass recovery in both treated and contralateral limbs. This was associated with changes in numerous cytokines in treated skeletal muscle and sera. Several factors we observe to be regulated were also shown to be regulated by STM in other studies, including ciliary neurotrophic factor (CNTF), IL-1β, IL-2, IL-3, IL-13, ICAM-1, and tumor necrosis factor alpha (TNF-α), whereas others are reported for the first time. Conclusions Our study adds further support for the role of manual therapy in musculoskeletal health and details molecular-level effects in both target tissue and circulation. STM may hold promise for recovering muscle mass and function related in conditions of atrophy such as age-related sarcopenia.
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Analyte Control HLS
A3,A4 Adiponectin/Acrp30 1 0.96
A5,A6 CCL2/JE/MCP‐11 1.18
A7,A8 CCL3/CCL4/MIP‐1α/β1 1.11
A9,A10 CCL5/RANTES 1 1.00
A11,A12 CCL11/Eotaxin 1 0.98
A13,A14 CCL17/TARC 1 1.05
A15,A16 CCL20/MIP‐3α1 0.90
A17,A18 CCL21/6Ckine 1 1.19
A19,A20 CCL22/MDC 1 1.69
A21,A22 Clusterin 1 1.04
B3,B4 CNTF 1 1.69
B5,B6 CX3CL1/Fractalkine 1 1.25
B7,B8 CXCL2/GROβ/MIP‐2/CINC‐3 1 0.97
B9,B10 CXCL7/ThymusChemokine‐1 1 0.66
B11,B12 Cyr61/CCN1 1 1.11
B13,B14 CystatinC 1 1.13
B15,B16 DPPIV/CD26 1 0.87
B17,B18 EGF 1 0.90
B19,B20 EG‐VEGF/PK1 1 1.24
B21,B22 Endostatin 1 0.85
C3,C4 FetuinA/AHSG 1 0.91
C5,C6 FGFacidic 1 1.06
C7,C8 FGF‐7/KGF 1 1.29
C9,C10 FGF‐21 1 1.07
C11,C12 Fibulin3 1 1.11
C13,C14 Flt‐3Ligand 1 1.07
C15,C16 Galectin‐1 1 1.06
C17,C18 Galectin‐3 1 1.25
C19,C20 G‐CSF 1 1.07
C21,C22 GDF‐15 1 0.87
D1,D2 GM‐CSF 1 0.77
D3,D4 Hepassocin 1 0.73
D5,D6 HGF 1 0.59
D7,D8 ICAM‐1/CD54 1 0.76
D9,D10 IFN‐γ 1 1.18
D11,D12 IGF‐I 1 0.64
D13,D14 IGFBP‐2 1 1.18
D15,D16 IGFBP‐3 1 0.85
SupplementalTable1.Comparisonofcytokinelevelsintissuehomogenatesof
quadricepsfromweight‐bearingcontrols(Control)versushindlimbsuspension(HLS)
groups.Totalproteinwaspooledatequalratiosforn=5Controlandn=6HLSanimals.
Dataaremeansignaldensityrelativetotheaveragereferencespotdensity
normalizedtoControl.Greenandpinkhighlightindicates≥25%increaseordecrease,
respectively,comparedtoControls.
D17,D18 IGFBP‐5 1 1.17
D19,D20 IGFBP‐6 1 1.19
D21,D22 IL‐1α/IL‐1F1 1 0.69
D23,D24 IL‐1β/IL‐1F2 1 1.03
E1,E2 IL‐1ra/IL‐1F3 1 0.99
E3,E4 IL‐2 1 0.73
E5,E6 IL‐3 1 0.76
E7,E8 IL‐4 1 0.95
E9,E10 IL‐6 1 1.27
E11,E12 IL‐13 1 1.36
E13,E14 IL‐17A 1 1.15
E15,E16 IL‐22 1 0.99
E17,E18 Jagged1 1 1.14
E19,E20 LIF 1 0.93
E21,E22 Lipocalin‐2/NGAL 1 0.66
E23,E24 LIX 1 1.12
F1,F2 MAG/Siglec‐4a 1 1.03
F3,F4 MMP‐2 1 1.01
F5,F6 MMP‐3 1 1.28
F7,F8 MMP‐9 1 1.24
F9,F10 Neprilysin/CD10 1 1.32
F11,F12 NOV/CCN3 1 1.01
F13,F14 NT‐3 1 1.03
F15,F16 NT‐4 1 0.85
F17,F18 Osteopontin(OPN) 1 1.00
F19,F20 Osteoprotegerin/TNFRSF11B 1 1.02
F21,F22 PDGF‐BB 1 0.76
F23,F24 Pref‐1/DLK1/FA1 1 1.09
G1,G2 Prolactin 1 0.80
G3,G4 RAGE 1 1.00
G5,G6 RBP4 1 1.04
G7,G8 Resistin 1 1.26
G9,G10 RGM‐A 1 1.56
G11,G12 SCF 1 1.32
G13,G14 SerpinE1/PAI‐1 1 1.19
G15,G16 TIM‐1/KIM‐1/HAVCR 1 1.06
G17,G18 TNF‐α 1 0.90
G19,G20 TWEAK/TNFSF12 1 0.98
G21,G22 VCAM‐1/CD106 1 0.74
G23,G24 VEGF 1 0.73
H5,H6 WISP‐1/CCN4 1 1.35
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Advances in sarcopenia: mechanisms, therapeutic targets, and intervention strategies
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Sarcopenia is a multifactorial condition characterized by loss of muscle mass. It poses significant health risks in older adults worldwide. Both pharmacological and non-pharmacological approaches are reported to address this disease. Certain dietary patterns, such as adequate energy intake and essential amino acids, have shown positive outcomes in preserving muscle function. Various medications, including myostatin inhibitors, growth hormones, and activin type II receptor inhibitors, have been evaluated for their effectiveness in managing sarcopenia. However, it is important to consider the variable efficacy and potential side effects associated with these treatments. There are currently no drugs approved by the Food and Drug Administration for sarcopenia. The ongoing research aims to develop more effective strategies in the future. Our review of research on disease mechanisms and drug development will be a valuable contribution to future research endeavors.
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Is moderate resistance training adequate for older adults with sarcopenia? A systematic review and network meta-analysis of RCTs
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Soft Tissue Manipulation Alters RANTES/CCL5 and IL-4 Cytokine Levels in a Rat Model of Chronic Low Back Pain
Preprint
Full-text available
  • Jul 2023
Low back pain (LBP) is a common musculoskeletal complaint that can impede physical function and mobility. Current management often involves pain medication, but there is a need for non-pharmacological and non-invasive interventions. Soft tissue manipulation (STM) such as massage has been shown to be effective in human subjects, but the molecular mechanisms underlying these findings are not well understood. In this paper, we evaluated potential changes in soft tissue levels of more than thirty pro- or anti-inflammatory cytokines following instrument-assisted STM (IASTM) in rats with chronic, induced LBP using Complete Freund’s Adjuvant. Our results indicate that IASTM is associated with reduced soft tissue levels of RANTES/CCL5 and increased soft tissue levels of IL-4, which are pro-inflammatory and anti-inflammatory factors, respectively, by 120 minutes post-treatment. IASTM was not associated with tissue-level changes in CXCL5/LIX (the murine homologue of IL-8), CXCL7, GM-CSF ICAM-1, IL1-ra, IL-6, IP-10/CXCL10, L-selectin, TNF-α, or VEGF at either 30- or 120 minutes post-treatment. Combined, our findings suggest that IASTM exerts tissue-level effects that are associated with improved clinical outcomes and potentially beneficial changes in pro/anti-inflammatory cytokines in circulation and at the tissue level.
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A Handheld Quantifiable Soft Tissue Manipulation Device for Tracking Real-Time Dispersive Force-Motion Patterns to Characterize Manual Therapy Treatment
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Resistance exercise as a treatment for sarcopenia: prescription and delivery
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  • AGE AGEING
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Quantifiable Soft Tissue Manipulation (QSTM™) – A novel modality to improve clinical manual therapy with objective metrics
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Full-text available
  • Nov 2021
Soft Tissue Manipulation (STM), a form of mechanotherapy, offers a clinical modality to examine and treat Neuromusculoskeletal (NMS) pain disorders and dysfunction. The, current STM practice is mostly subjective and reliant on anecdotal patient feedback and lacks quantification with objective metrics. This paper proposes Quantifiable Soft Tissue Manipulation (QSTM™), a sensor based computerized technological advancement in Soft tissue examination and treatment enabling new standard of practice in manual therapy. This novel medical device technology aims to produce optimum STM prescriptions using ergonomic, portable, handheld medical tools with specially contoured tips designed to palpate and assess tissue anomalies of specific musculoskeletal conditions. QSTM™ captures three-dimensional forces and motion of the mechatronic handheld tools to quantify STM treatment parameters, such as (resultant force, force application angle, rate, direction, and treatment time). Clinical practice using QSTM™ facilitates real-time visual feedback of treatment metrics and subsequent treatment documentation for comparison and analysis on a Windows based computer software (Q-Ware©). Pre-clinical testing using the QSTM™ medical device system clearly identifies inconsistencies among practitioners and distinguishes STM practice variabilities. Thus, QSTM™ is an apt tool for soft tissue treatment assessment, analysis, and individualized prescriptions for targeted STM dosing and commercialization.
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Does the combination of resistance training and a nutritional intervention have a synergic effect on muscle mass, strength, and physical function in older adults? A systematic review and meta-analysis
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Full-text available
  • Nov 2021
  • BMC Geriatr
Background Health-promoting interventions are important for preventing frailty and sarcopenia in older adults. However, there is limited evidence that nutritional interventions yield additional effects when combined with resistance training. This systematic review and meta-analysis aimed to compare the effectiveness of nutritional interventions with resistance training and that of resistance training alone. Methods Randomized controlled trials published in peer-reviewed journals prior to July 2020 were retrieved from databases and other sources. The articles were screened according to the inclusion and exclusion criteria. The methodological quality of the included studies was assessed using Cochrane’s risk of bias tool 2. A meta-analysis was performed using the RevMan 5.4 program and STATA 16 program. Results A total of 22 studies were included in the meta-analysis. The results of the meta-analysis showed no significant differences between groups in muscle mass, muscle strength, or physical functional performance. In the subgroup analysis regarding the types of nutritional interventions, creatine showed significant effects on lean body mass ( n = 4, MD 2.61, 95% CI 0.51 to 4.72). Regarding the other subgroup analyses, there were no significant differences in appendicular skeletal muscle mass ( p = .43), hand grip strength ( p = .73), knee extension strength ( p = .09), chair stand test results ( p = .31), or timed up-and-go test results ( p = .31). In the meta-regression, moderators such as the mean age of subjects and duration of interventions were not associated with outcome variables. Conclusions This meta-analysis showed that nutritional interventions with resistance training have no additional effect on body composition, muscle strength, or physical function. Only creatine showed synergistic effects with resistance training on muscle mass. Trial registration CRD42021224843 .
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Age-associated inflammation and implications for skeletal muscle responses to exercise
Article
  • Apr 2023
Aging is associated with profound alterations in skeletal muscle, including loss of muscle mass and function, local inflammation, altered mitochondrial physiology, and attenuated anabolic responses to exercise termed anabolic resistance. "Inflammaging," the chronic, low-grade inflammation associated with aging, may contribute to many of the age-related derangements in skeletal muscle, including its ability to respond to exercise and nutritional stimuli. Inflammation and exercise are closely intertwined in numerous ways. A single bout of muscle-damaging exercise stimulates an acute inflammatory response in the skeletal muscle that is essential for muscle repair and regeneration; however, the chronic systemic and local inflammation associated with aging may impair acute inflammatory and anabolic responses to exercise. In contrast, exercise training is anti-inflammatory, targeting many of the potential root causes of inflammaging. In this review, we discuss the interplay between inflammation and exercise in aging and highlight potential therapeutic targets for improving adaptive responses to exercise in older adults.
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Age-Related Susceptibility to Muscle Damage Following Mechanotherapy in Rats Recovering From Disuse Atrophy
Article
  • Jun 2021
The inability to fully recover lost muscle mass following periods of disuse atrophy predisposes older adults to lost independence and poor quality of life. We have previously shown that mechanotherapy at a moderate load (4.5 N) enhances muscle mass recovery following atrophy in adult, but not older adult rats. We propose that elevated transverse stiffness in aged muscle inhibits the growth response to mechanotherapy and hypothesize that a higher load (7.6 N) will overcome this resistance to mechanical stimuli. F344/BN adult and older adult male rats underwent 14-days of hindlimb suspension, followed by 7-days of recovery with (RE+M) or without (RE) mechanotherapy at 7.6 N on gastrocnemius muscle. The 7.6 N load was determined by measuring transverse passive stiffness and linearly scaling up from 4.5 N. No differences in protein turnover or mean fiber cross sectional area were observed between RE and RE+M for older adult rats or adult rats at 7.6 N. However, there was a higher number of small muscle fibers present in older adult, but not adult rats, which was explained by a 16-fold increase in the frequency of small fibers expressing embryonic myosin heavy chain. Elevated central nucleation, satellite cell abundance, and dystrophin -/laminin + fibers were present in older adult rats only following 7.6 N, while 4.5 N did not induce damage at either age. We conclude that age is an important variable when considering load used during mechanotherapy and age-related transverse stiffness may predispose older adults to damage during the recovery period following disuse atrophy.
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Soft Tissue Manipulation May Attenuate Inflammation, Modulate Pain, and Improve Gait in Conscious Rodents With Induced Low Back Pain
Article
  • Jan 2021
Introduction Low back pain (LBP) is common in warfighters. Noninvasive interventions are necessary to expedite return-to-function. Soft tissue manipulation, for example, massage, is a method used to treat LBP. Instrument-assisted soft tissue manipulation (IASTM) uses a rigid device to mobilize the tissue. This study explored the effects of IASTM on pain, function, and biomarkers. Methods Sprague-Dawley rats (n = 44) were randomized to groups (n = 6/grp): (A) cage control; (B) 3 days (3d) postinjury (inj), untreated; (C) 3d inj, < 30-minute post-IASTM treatment; (D) 3d inj, 2 hours (2h) post-IASTM; (E) 14 days (14d) inj, untreated; (F) 14d inj, < 30-minute post-IASTM; and (G) 14d inj, 2h post-IASTM. Researchers induced unilateral LBP in Sprague-Dawley rats using complete Freund’s adjuvant injection. Conscious rodents received IASTM for 5 min/session once at 3 days or 3×/week × 2weeks (6× total) over 14 days. Biomarker plasma levels were determined in all groups, while behavioral outcomes were assessed in two groups, D and G, at three time points: before injury, pre-, and post-IASTM treatment. Circulating mesenchymal stem cell levels were assessed using flow cytometry and cytokine plasma levels assayed. Results The back pressure pain threshold (PPT) lowered bilaterally at 3 days postinjury (P < .05), suggesting increased pain sensitivity. IASTM treatment lowered PPT more on the injured side (15.8%; P < 0.05). At 14 days, back PPT remained lower but similar side to side. At 3 days, paw PPT increased 34.6% in the contralateral rear limb following treatment (P < .01). Grip strength did not vary significantly. Gait coupling patterns improved significantly (P < .05). Circulating mesenchymal stem cell levels altered significantly postinjury but not with treatment. Neuropeptide Y plasma levels increased significantly at 3 days, 2h post-IASTM (53.2%) (P < .05). Interleukin-6 and tumor necrosis factor-alpha did not vary significantly. At 14 days, regulated on activation, normal T cell expressed and secreted decreased significantly <30-minute post-IASTM (96.1%, P < .002), while IL-10 trended upward at 2h (53.1%; P = .86). Conclusions LBP increased pain sensitivity and diminished function. IASTM treatment increased pain sensitization acutely in the back but significantly reduced pain sensitivity in the contralateral rear paw. Findings suggest IASTM may positively influence pain modulation and inflammation while improving gait patterns. Soft tissue manipulation may be beneficial as a conservative treatment option for LBP.
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