Figure A — Simplified time course (schematic) of cellular infiltration & functional markers after eccentric exercise

Notes: This Plotly schematic translates the review's time windows into a single visual: neutrophil activity is early (1–24 h), macrophage influx and phenotype transition peak later (48 h–7 d), DOMS and swelling follow distinct but overlapping kinetics, and maximal voluntary contraction (MVC) recovery typically lags behind soreness resolution — all described in Peake et al. (2017). Citations below provide the source material for these temporal windows and functional markers.

Key evidence claims (each claim is cited)

• Neutrophils are mobilized and detectable in muscle microvasculature within 1–24 h post‑eccentric exercise; extracellular leukocyte accumulation in muscle histology is commonly observed 24–48 h post‑exercise (Peake et al., review timeline).
• Pro‑inflammatory (M1) macrophages dominate early; a transition to anti‑inflammatory (M2) macrophages around ~24–72 h (and beyond) is crucial for satellite cell proliferation → differentiation and ECM remodeling (Macrophage phenotype switching review).
• Cytokine/chemokine transcription in muscle (e.g., IL‑6, CXCL8/IL‑8, CCL2/MCP‑1) shows early (1–4 h) and later (~24 h) mRNA peaks; protein‑level intramuscular data are sparser (Cytokine time windows in muscle).
• The repeated‑bout effect (prior eccentric exposure or low‑intensity preconditioning) reduces subsequent leukocyte recruitment and dampens pro‑inflammatory gene expression — a robust human phenomenon (Repeated‑bout effect summary).
• Interventions: massage, compression and cold water immersion give consistent symptomatic benefit (soreness reduction) and sometimes modest strength recovery improvements; NSAIDs commonly do not improve intramuscular inflammatory outcomes and can impede regeneration in some contexts (Massage reduces inflammatory signaling & Intervention evidence summary).

Critical appraisal — strengths and limitations

• Strengths: authoritative synthesis integrating human biopsy, transcriptomics and animal mechanistic work; clearly identifies time windows and key cell types; balanced discussion of interventions and cautions about suppressing beneficial inflammation (Review balanced strengths).
• Limitations (paper itself): as a mini‑review it necessarily depends on heterogeneous primary literature — small human sample sizes, diverse exercise protocols, different biopsy timing and notable species differences for animal models; objective protein‑level intramuscular cytokine quantification is limited; biopsy trauma may confound local inflammation (Review limitations).
• Blindspots & biases to watch: most human data are young, healthy adults — elderly, chronically inflamed, or diseased populations may respond differently (important for NSAID/polyphenol guidance); publication bias can inflate apparent benefits for some nutraceuticals; some intervention trials have industry ties (e.g., older NSAID pharmaceutical trials) — interpret with caution (Gaps and bias callout).

Counter‑evidence that would change the review's conclusions

1. Large, well‑controlled human trials showing that early blockade of specific inflammatory mediators (e.g., targeted cytokine antagonists) accelerates regeneration and improves long‑term function would challenge the view that early inflammation is beneficial.
2. Comprehensive intramuscular protein time‑series (not just mRNA) in humans demonstrating no M1→M2 macrophage phenotype shift after exercise would force reappraisal of macrophage plasticity in human EIMD.
3. High‑quality negative replications of purported benefits from polyphenols/omega‑3s in large RCTs would down‑weight nutraceutical claims currently supported mainly by small or animal studies (Nutriceutical evidence caution).

Figure B — Priority experiments to fill gaps (visual roadmap)

Rationale: experiments emphasize human in vivo intramuscular protein kinetics (to move beyond transcript proxies), large randomized controlled intervention trials in understudied populations (older adults), and targeted modulation of macrophage phenotypes to test causality.

Concise practical/interpretive takeaways

• Inflammation after exercise is usually adaptive and time‑dependent; blunt suppression of early inflammation may impair regeneration in young healthy muscle (Inflammation often adaptive).
• Non‑pharmacological therapies (massage, compression, cold water immersion) have consistent symptom benefits and occasional performance recovery advantages; their mechanistic effects on intramuscular inflammation are variable and incompletely characterized (Massage mechanism study).
• Translational caution: much mechanistic detail derives from rodent or toxin injury models that can overstate necrosis compared to voluntary eccentric exercise in humans; design human time‑series and interventional RCTs before broad clinical recommendations.

Primary citations used in this review (detailed extracts)

Peake et al., review

Crane et al., massage trial

Macrophage–myogenesis review