The Role of Mitochondria in Mediation of Skeletal Muscle Repair

Muscles, Journal Year: 2023, Volume and Issue: 2(2), P. 119 - 163

Published: March 24, 2023

Musculoskeletal health is directly linked to independence and longevity, but disease aging impairs muscle mass health. Complete repair after a pathological or physiological injury critical for maintaining function, yet compromised disuse, in conditions such as metabolic diseases, cancer, aging. Regeneration of damaged tissue critically dependent upon achieving the optimal function satellite cells (muscle stem cells, MSCs). MSC remodeling highly its microenvironment, MSCs, which on functional capacity their mitochondria. Muscle energy demanding mitochondria provide primary source production during regeneration. However, induce mitochondrial dysfunction, limits Nevertheless, role likely extends beyond ATP could potentially important regulatory signaling MSCs from injury. The scope current research regeneration molecules exosomes, largely with goal understanding ways improve function. This review focuses skeletal myogenesis/regeneration repair. A therapeutic strategy improving number will be discussed means enhancing Highlights: (a). Mitochondrial dysfunction regeneration; (b). cell (MSC) can modulated by mitochondria; (c). Enhancing may an

Language: Английский

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Resistance wheel running improves contractile strength, but not metabolic capacity, in a murine model of volumetric muscle loss injury

Experimental Physiology, Journal Year: 2023, Volume and Issue: 108(10), P. 1282 - 1294

Published: Aug. 1, 2023

The primary objective of this study was to determine if low- or high-resistance voluntary wheel running leads functional improvements in muscle strength (i.e., isometric and isokinetic torque) metabolic function permeabilized fibre bundle mitochondrial respiration) after a volumetric loss (VML) injury. C57BL/6J mice were randomized into one four experimental groups at age 12 weeks: uninjured control, VML untreated (VML), low-resistance (VML-LR) (VML-HR). All mice, excluding the uninjured, subject unilateral injury plantar flexor muscles began 3 days post-VML. At 8 weeks post-VML, peak torque greater compared all VML-injured groups, but both VML-LR VML-HR had (∼32%) VML. less there no statistical difference among VML, VML-HR. No differences cumulative distance observed between groups. Because adaptations attributed gastrocnemius mass, atrophy- hypertrophy-related protein content post-translational modifications explored via immunoblot; however, results inconclusive. Permeabilized oxygen consumption 22% Furthermore, neither group demonstrated change relative biogenesis transcription factor, peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α). These indicate that resistance alone only has modest benefits muscle. NEW FINDINGS: What is central question study? Does initiation regimen following improve capacity skeletal muscle? main finding its importance? Resistance led mass with did not result full recovery. Neither nor associated respiration despite runners having whole-body treadmill endurance capacity, suggesting resilience may be suitable adjuvant rehabilitation strategy, does fully mitigate pathology.

Language: Английский

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Regenerative rehabilitation: Navigating the gap between preclinical promises and clinical realities for treating trauma‐induced volumetric muscle loss

The Journal of Physiology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 28, 2025

Abstract Regenerative rehabilitation is an emerging interdisciplinary field that combines regenerative medicine principles with science to improve recovery in musculoskeletal trauma cases such as volumetric muscle loss (VML). This article reviews preclinical and clinical studies, aiming bridge the gap between these domains, summarize recent advancements identify areas for further exploration. The review delves into which explore potential of approaches, including cellular acellular scaffolds, augment exercise‐based rehabilitation. These studies demonstrate can aid functional post‐VML through various mechanisms modulation fibrosis, angiogenesis, myogenesis innervation. However, approach differs significantly, involving diverse exercise therapy regimens both before after surgical interventions. To date, only extracellular matrix scaffolds have been combined physical VML‐injured patients, resulting modest improvements recovery. nascent but has seen noteworthy progress, ample room improvement. also highlights need closer collaboration researchers fields tissue engineering, orthopaedic surgery outcomes following traumatic injuries. image

Language: Английский

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Inhibition of ErbB2 mitigates secondary denervation after traumatic muscle injury

The Journal of Physiology, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Abstract Secondary denervation has recently been described as part of the sequela volumetric muscle loss (VML) injury, occurring along with a significantly elevated neurotrophic response, specifically neuregulin‐1 (NRG1). This may contribute to chronic functional impairments associated representing an overlooked treatment target. Thus, though paradoxical, goal this study was pharmacologically reduce signalling after VML using monoclonal antibody (Herceptin) that inhibits ErbB2 receptors. We also assessed whether inhibition combined myogenic (i.e. minced graft) would have synergistically beneficial effect on function. Adult male Lewis rats underwent surgical induction tibialis anterior injury and were randomized into one four groups: untreated, Herceptin, graft + comparisons contralateral (uninjured) control muscle. Rats receiving Herceptin administered drug (8 mg/kg i.p. ) at time surgery thrice per week for duration (48 days). Terminally individual NMJs quantitatively evaluated, maximal in vivo torque tested. fully restored normal rates NMJ innervation morphology improved de novo myofibres muscle‐graft treatment. However did not improve skeletal function alone or combination conclude is promising therapeutic option treating yet more work needed optimize translation characteristics recover image Key points In cases complex traumatic musculoskeletal such (VML), endogenous ability regenerate lost. Innervation, connection motor axon each myofibre, necessary component myofibre survival contractile function, which disrupted VML. Paradoxically monocolonal inhibitor (receptor tyrosine kinase ErbB2; Herceptin) shown regeneration rodent models nerve injury. Here we show pharmaceutical following rat model improves innervation; however it correspondingly Although ineffective its noteworthy should be considered adjunctive combinatorial therapy option.

Language: Английский

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Advancing β-adrenoreceptor agonism for recovery after volumetric muscle loss through regenerative rehabilitation and biomaterial delivery approaches

Regenerative Biomaterials, Journal Year: 2025, Volume and Issue: 12

Published: Jan. 1, 2025

Abstract Volumetric muscle loss (VML) injury results in the unrecoverable of mass and contractility. Oral delivery formoterol, a β2-adrenergic receptor agonist, produces modest recovery contractility VML-injured mice. The objective this study was to determine if regenerative rehabilitation paradigm or medicine could enhance muscle. Regenerative involved oral formoterol combined with voluntary wheel running. direct using non-biodegradable poly(ethylene glycol) biomaterial. To approaches were effective at 8 weeks post-injury, mass, contractile function, metabolic histological evaluations used. One model rehabilitation, which delayed until 1 month resulted greater contractility, permeabilized fiber mitochondrial respiration compared untreated Histologically, these mice had evidence total number oxidative fibers; however, they also percentage densely packed collagen. produced mice; biomaterial associated fewer fibers lower quality (i.e. mass-normalized contractility). conclusions reached from are: (i) strategies utilizing require further optimization but showed promising outcomes; (ii) general, β-adrenergic agonism continues be physiologically supportive intervention improve function after VML injury.

Language: Английский

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Differential evaluation of neuromuscular injuries to understand re-innervation at the neuromuscular junction

Experimental Neurology, Journal Year: 2024, Volume and Issue: 382, P. 114996 - 114996

Published: Oct. 10, 2024

Peripheral nerve-crush injury is a well-established model of neuromuscular junction (NMJ) denervation and subsequent re-innervation. Functionally, the skeletal muscle follows similar pattern as neural recovery, with immediate loss force production that steadily improves in parallel rates On other hand, traumatic to itself, specifically volumetric (VML), results an irrecoverable function. Recent work has indicated significant impairments NMJ following this appear chronic nature, alongside lack functional recovery. Thus, goal study was compare effects nerve on remodeling. Even numbers adult male female mice were used three experimental groups: Naïve, crush, VML injury; terminal timepoints: 3-, 48-, 112-days post-injury. Confirming assumed recoverability two models, we found vivo maximal torque fully restored but remained at deficit VML. Compared Naïve injury, aberrantly high trophic signaling (e.g., neuregulin-1) supporting cells, including Schwann cells sub-synaptic nuclei. In some cases, sex differences detected, higher innervation females than males. Both crush display changes morphology, such increased fragmentation sprouting, highlighting potential for modeling regeneration adulthood, established nerve-injury models.

Language: Английский

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The bioenergetic “CK Clamp” technique detects substrate-specific changes in mitochondrial respiration and membrane potential during early VML injury pathology

Frontiers in Physiology, Journal Year: 2023, Volume and Issue: 14

Published: April 4, 2023

Volumetric muscle loss (VML) injuries are characterized by non-recoverable of tissue resulting in contractile and metabolic dysfunction. The characterization dysfunction volumetric loss-injured has been interpreted from permeabilized myofiber respiration experiments involving saturating ADP levels non-physiologic ATP:ADP concentration ratios. extent to which this testing condition obscures the analysis mitochondrial (dys) function after injury is unclear. An alternative approach described that leverages enzymatic reaction creatine kinase phosphocreatine assess membrane potential at clamped physiologic ratios, “CK Clamp.” objective study was validate CK Clamp detect differences may exist between uninjured muscles 1, 3, 5, 7, 10, 14 days post-injury. maintains bioenergetic features approach, i.e., rate (JO 2 ) titters down more polarized with increasing Pyruvate/malate/succinate-supported JO significantly less all timepoints compared controls (−26% −84%, p < 0.001) electron conductance day 1 (−60%), 5 (−52%), 7 (−35%), 10 (−59%), (−41%) ( 0.001). Palmitoyl-carnitine/malate-supported were affected following injury. loss-injury also corresponded a across ratios (pyruvate palmitoyl-carnitine, respectively) (+5%, This supports previous characterizations validates as tool investigate bioenergetics traumatically-injured muscle.

Language: Английский

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Exploring skeletal muscle tolerance and whole‐body metabolic effects of FDA‐approved drugs in a volumetric muscle loss model

Physiological Reports, Journal Year: 2023, Volume and Issue: 11(12)

Published: June 1, 2023

Volumetric muscle loss (VML) is associated with persistent functional impairment due to a lack of de novo regeneration. As mechanisms driving the regeneration continue be established, adjunctive pharmaceuticals address pathophysiology remaining may offer partial remediation. Studies were designed evaluate tolerance and efficacy two FDA-approved pharmaceutical modalities tissue after VML injury: (1) nintedanib (an anti-fibrotic) (2) combined formoterol leucine (myogenic promoters). Tolerance was first established by testing low- high-dosage effects on uninjured skeletal mass myofiber cross-sectional area in adult male C57BL/6J mice. Next, tolerated doses tested VML-injured mice an 8-week treatment period for their ability modulate strength whole-body metabolism. The most salient findings indicate that plus mitigated mass, number, lipid oxidation, strength, resulted higher metabolic rate (p ≤ 0.016); did not exacerbate or correct aspects VML. This supports ongoing optimization efforts, including scale-up evaluations large animal models

Language: Английский

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Differential effects of Western diet and traumatic muscle injury on skeletal muscle metabolic regulation in male and female mice

Journal of Cachexia Sarcopenia and Muscle, Journal Year: 2023, Volume and Issue: 14(6), P. 2835 - 2850

Published: Oct. 25, 2023

Language: Английский

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In Sequence Anti-Fibrotic Treatment and Rehabilitation following Volumetric Muscle Loss Injury

Advances in Wound Care, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 9, 2024

Mitigation of local pathologic fibrotic tissue deposition is a target area interest for volumetric muscle loss (VML); nintedanib has shown promise reduction fibrosis following VML. Herein studies investigate how in sequence anti-fibrotic treatment administered immediately VML and delayed rehabilitation could improve functional recovery after

Language: Английский

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