Muscle from aged rats is resistant to mechanotherapy during atrophy and reloading

Lawrence, Marcus M.; Pelt, Douglas W. Van; Confides, Amy L.; Hettinger, Zachary R.; Hunt, E. Raymond; Reid, Justin J.; Laurin, Jaime L.; Peelor, Frederick F.; Butterfield, Timothy A.; Miller, Benjamin F.; Dupont‐Versteegden, Esther E.

doi:10.1007/s11357-020-00215-y

Cited by 7 publications

(6 citation statements)

References 76 publications

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“…Furthermore, it is well known that muscle and its associated connective tissues stiffen with age, leading to alterations in force transmission ( 51 – 53 ), and this may make aged myofibers more susceptible to load-induced injury, potentially provoking a heightened release of myokines from the injured tissue in response to ML. The lack of functional improvement with ML in aged animals found here aligns with some studies in the literature that showed that aged muscle was unresponsive to massage-like therapy ( 54 , 55 ) but contradicts the findings of others ( 18 , 56 , 57 ). Because the methodologies used in past studies were highly inconsistent, these conflicting results may relate to the type of mechanical stimulus, loading regimen, injury model, and animal strain/age.…”

Section: Discussionsupporting

confidence: 86%

Anti-inflammatory therapy enables robot-actuated regeneration of aged muscle

et al. 2023

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Robot-actuated mechanical loading (ML)–based therapies (“mechanotherapies”) can promote regeneration after severe skeletal muscle injury, but the effectiveness of such approaches during aging is unknown and may be influenced by age-associated decline in the healing capacity of skeletal muscle. To address this knowledge gap, this work used a noninvasive, load-controlled robotic device to impose highly defined tissue stresses to evaluate the age dependence of ML on muscle repair after injury. The response of injured muscle to robot-actuated cyclic compressive loading was found to be age sensitive, revealing not only a lack of reparative benefit of ML on injured aged muscles but also exacerbation of tissue inflammation. ML alone also disrupted the normal regenerative processes of aged muscle stem cells. However, these negative effects could be reversed by introducing anti-inflammatory therapy alongside ML application, leading to enhanced skeletal muscle regeneration even in aged mice.

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Section: Discussionsupporting

confidence: 86%

Anti-inflammatory therapy enables robot-actuated regeneration of aged muscle

et al. 2023

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“…Protein fractions were derivatized for analysis of deuterium enrichment in alanine using Gas Chromatography-Mass Spectroscopy (7890A GC-Agilent 5975C MS, Agilent, Santa Clara, CA). 35 To determine the precursor pool enrichment, plasma samples were prepared for analysis of deuterium enrichment on a liquid water isotope analyzer (Los Gatos Research, Los Gatos, CA, USA) using 0%–12% deuterium standards. 36 The precursor enrichment of alanine was then adjusted by mass isotopomer distribution analysis.…”

Section: Methodsmentioning

confidence: 99%

A Novel Stable Isotope Approach Demonstrates Surprising Degree of Age-Related Decline in Skeletal Muscle Collagen Proteostasis

et al. 2021

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Age-related deterioration in turnover of collagen proteins accelerates extracellular matrix (ECM) fibrosis and hinders adaptation to external stimuli. This project sought to understand factors that increase skeletal muscle fibrosis with age by studying what we term the dynamic protein pool. We hypothesized that the dynamic protein pool size of muscle collagen decreases with age, thus indicating a decrease in proteostatic maintenance (i.e., ability to maintain proteostasis), and that failure to account for these changes impacts the interpretation of tracer-measured synthesis rates. We used deuterium oxide (D2O) labeling for up to 60 days in adult (6 months) and old (23 months) mice. The dynamic protein pool in adult skeletal muscle was 65% in tibialis anterior (TA), but only 28% in gastrocnemius (Gastroc). In aged muscle, the dynamic protein pool was further decreased to only 35% and 14% for TA and Gastroc, respectively. We showed that this loss in dynamic pool size was associated with increases in markers of fibrosis and decreased proteostatic maintenance. We demonstrate that aged muscle has higher rates of collagen protein synthesis and lower rates of collagen protein breakdown, which causes collagen accumulation. We further demonstrated that the normal assumption of complete protein renewal and the standard practice of taking a single sample with isotope labeling have profound impacts on interpretation of the genesis of fibrosis. Strategies to maintain muscle function with aging should focus on the dynamic protein pool with attention to methodological strategies to assess those changes.

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“…We determined deuterium incorporation into protein of GA, TA and SOL muscles as previously described 11,23,24 . To determine ribosomal biogenesis, we assessed RNA synthesis using isolated RNA as previously described 8,25 .…”

Section: Methodsmentioning

confidence: 99%

“…We determined deuterium incorporation into protein of GA, TA and SOL muscles as previously described. 11,23,24 To determine ribosomal biogenesis, we assessed RNA synthesis using isolated RNA as previously described. 8,25 Derivatized samples of alanine and RNA were run on an Agilent 7890A GC coupled to an Agilent 5975C MS. 23,24 Body water enrichment was determined on serum using a Liquid Water Isotope Analyzer (LWIA-45-EP, Los Gatos Research, San Jose, CA).…”

Section: Protein and Rna Turnover Proteomics And Bioinformaticsmentioning

confidence: 99%

“…11,23,24 To determine ribosomal biogenesis, we assessed RNA synthesis using isolated RNA as previously described. 8,25 Derivatized samples of alanine and RNA were run on an Agilent 7890A GC coupled to an Agilent 5975C MS. 23,24 Body water enrichment was determined on serum using a Liquid Water Isotope Analyzer (LWIA-45-EP, Los Gatos Research, San Jose, CA). 26 For protein and RNA turnover, we calculated the rise to plateau of fraction new over the time-course according to our previously published study.…”

Section: Protein and Rna Turnover Proteomics And Bioinformaticsmentioning

confidence: 99%

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Impaired proteostatic mechanisms other than decreased protein synthesis limit old skeletal muscle recovery after disuse atrophy

Fuqua,

Lawrence,

Hettinger

et al. 2023

J cachexia sarcopenia muscle

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BackgroundSkeletal muscle mass and strength diminish during periods of disuse but recover upon return to weight bearing in healthy adults but are incomplete in old muscle. Efforts to improve muscle recovery in older individuals commonly aim at increasing myofibrillar protein synthesis via mammalian target of rapamycin (mTOR) stimulation despite evidence demonstrating that old muscle has chronically elevated levels of mammalian target of rapamycin complex 1 (mTORC1) activity. We hypothesized that protein synthesis is higher in old muscle than adult muscle, which contributes to a proteostatic stress that impairs recovery.MethodsWe unloaded hindlimbs of adult (10‐month) and old (28‐month) F344BN rats for 14 days to induce atrophy, followed by reloading up to 60 days with deuterium oxide (D2O) labelling to study muscle regrowth and proteostasis.ResultsWe found that old muscle has limited recovery of muscle mass during reloading despite having higher translational capacity and myofibrillar protein synthesis (0.029 k/day ± 0.002 vs. 0.039 k/day ± 0.002, P < 0.0001) than adult muscle. We showed that collagen protein synthesis was not different (0.005 k (1/day) ± 0.0005 vs. 0.004 k (1/day) ± 0.0005, P = 0.15) in old compared to adult, but old muscle had higher collagen concentration (4.5 μg/mg ± 1.2 vs. 9.8 μg/mg ± 0.96, P < 0.01), implying that collagen breakdown was slower in old muscle than adult muscle. This finding was supported by old muscle having more insoluble collagen (4.0 ± 1.1 vs. 9.2 ± 0.9, P < 0.01) and an accumulation of advanced glycation end products (1.0 ± 0.06 vs. 1.5 ± 0.08, P < 0.001) than adult muscle during reloading. Limited recovery of muscle mass during reloading is in part due to higher protein degradation (0.017 1/t ± 0.002 vs. 0.028 1/t ± 0.004, P < 0.05) and/or compromised proteostasis as evidenced by accumulation of ubiquitinated insoluble proteins (1.02 ± 0.06 vs. 1.22 ± 0.06, P < 0.05). Last, we showed that synthesis of individual proteins related to protein folding/refolding, protein degradation and neural‐related biological processes was higher in old muscle during reloading than adult muscle.ConclusionsOur data suggest that the failure of old muscle to recover after disuse is not due to limitations in the ability to synthesize myofibrillar proteins but because of other impaired proteostatic mechanisms (e.g., protein folding and degradation). These data provide novel information on individual proteins that accumulate in protein aggregates after disuse and certain biological processes such as protein folding and degradation that likely play a role in impaired recovery. Therefore, interventions to enhance regrowth of old muscle after disuse should be directed towards the identified impaired proteostatic mechanisms and not aimed at increasing protein synthesis.

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Muscle from aged rats is resistant to mechanotherapy during atrophy and reloading

Cited by 7 publications

References 76 publications

Anti-inflammatory therapy enables robot-actuated regeneration of aged muscle

Anti-inflammatory therapy enables robot-actuated regeneration of aged muscle

A Novel Stable Isotope Approach Demonstrates Surprising Degree of Age-Related Decline in Skeletal Muscle Collagen Proteostasis

Impaired proteostatic mechanisms other than decreased protein synthesis limit old skeletal muscle recovery after disuse atrophy

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