Mitochondria-cytokine crosstalk following skeletal muscle injury and disuse: a mini-review

Abstract

Skeletal muscle mitochondria are highly adaptable, highly dynamic organelles that maintain the functional integrity of the muscle fiber by providing ATP for contraction and cellular homeostasis (e.g., Na⁺/K⁺ ATPase). Emerging as early modulators of inflammation, mitochondria sense and respond to cellular stress. Mitochondria communicate with the environment, in part, by release of physical signals called mitochondrial-derived damage-associated molecular patterns (mito-DAMPs) and deviation from routine function (e.g., reduced ATP production, Ca²⁺ overload). When skeletal muscle is compromised, mitochondria contribute to an acute inflammatory response necessary for myofibril regeneration; however, exhaustive signaling associated with altered or reduced mitochondrial function can be detrimental to muscle outcomes. Here, we describe changes in mitochondrial content, structure, and function following skeletal muscle injury and disuse and highlight the influence of mitochondria-cytokine crosstalk on muscle regeneration and recovery. Although the appropriate therapeutic modulation following muscle stressors remains unknown, retrospective gene expression analysis reveals that interleukin-6 (IL-6), interleukin-1β (IL-1β), chemokine C-X-C motif ligand 1 (CXCL1), and monocyte chemoattractant protein 1 (MCP-1) are significantly upregulated following three unique muscle injuries. These cytokines modulate mitochondrial function and execute bona fide pleiotropic roles that can aid functional recovery of muscle, however, when aberrant, chronically disrupt healing partly by exacerbating mitochondrial dysfunction. Multidisciplinary efforts to delineate the opposing regulatory roles of inflammatory cytokines in the muscle mitochondrial environment are required to modulate regenerative behavior following skeletal muscle injury or disuse. Future therapeutic directions to consider include quenching or limited release of mito-DAMPs and cytokines present in cytosol or circulation.

INTRODUCTION

Throughout life, skeletal muscle is frequently injured and rebuilt. Upon mechanical disruption to the sarcolemma, myofibers exhibit an endogenous capacity for regeneration (i.e., tissue plasticity) in which normally quiescent myoblasts differentiate in a similar manner as embryogenic myogenesis, integrate into the injury site, and fully restore muscle function. Remarkably, in acute injury cases, the regenerated myofibers become indistinguishable from uninjured and, in cases of exercise-induced injury, demonstrate greater resiliency to similar exercise type, intensity, and duration (1). Although the intricacies of skeletal muscle plasticity and regeneration following exercise-induced [see review (1)] and traumatic injuries [see review (2)] are out of scope for this review, these processes involve concerted action across multiple cell types and organelles, e.g., mitochondria.

Although mitochondria are most known for their fundamental role in aerobic metabolism, they are also extensively involved in maintaining muscle cell homeostasis through regulation of energy, ion, and redox systems. As highly plastic organelles, mitochondria can adapt or maladapt depending on the intensity and duration of a cellular stress. Inflammation is a common element to all forms of muscle damage necessary in acute form for subsequent functional recovery. Specifically, inflammatory cell involvement via chemotactic signals (e.g., IL-6, IL-1β, TNF-α), angiogenesis for early wound healing, noxious stimulus removal, phagocytosis of damaged tissues, and satellite cell migration and differentiation are examples of the positive role that inflammation can have on the regeneration process. However, excessive or prolonged inflammation results in deleterious effects and leads to tissue destruction (3).

Mitochondria are emerging as central modulators of inflammation, which govern fundamental cellular response to stressors (3, 4). Damaged or dysfunctional mitochondria release signals known as mitochondrial-derived damage-associated molecular patterns (mito-DAMPs), which are recognized similarly to their bacterial constituents (PAMPs) by the innate immune system and modulate postinjury inflammatory cell recruitment as well as cytokine release (4, 5). When skeletal muscle is compromised, mitochondria contribute to an acute inflammatory response necessary for myofibril regeneration; however, exhaustive signaling associated with dysfunctional mitochondria can be detrimental to muscle outcomes. Namely, excess mito-DAMP release propagates pro-inflammatory processes at the site of injury and exacerbates maladaptive responses to oxidative stress which impede functional muscle recovery. Although a full description of pro- and anti-inflammatory cascades is beyond the scope of this mini-review, we acknowledge these processes are mechanistically and temporally complex and often concurrent.

Herein, we describe how mitochondrial content, structure, and function are disrupted following skeletal muscle injury and disuse, and then highlight the role of mitochondria-cytokine crosstalk in promoting or exacerbating functional recovery.

SKELETAL MUSCLE INJURY AND DISUSE IMPACT MITOCHONDRIA

Outcome Measurements of Mitochondrial Content, Structure, and Function

Mitochondrial health is largely understood by determination of content, structure, and/or function. Although these mitochondrial network attributes are not mutually exclusive, e.g., their bioenergetic links have been well described (6), they each have unique outcome measurements that reflect characteristically on the quality of the mitochondria. Mitochondrial function can be inferred by mitochondrial enzyme kinetics (e.g., pyruvate dehydrogenase activity), mitochondrial respiration (i.e., oxygen consumption), mitochondrial membrane potential (Δψ), and reactive oxygen species (ROS) production. As these biochemical and physiological processes are connected, it is common for studies to include several of these outcomes. Mitochondrial dynamics refers to the fission and fusion proteins responsible for maintaining the structural integrity of the mitochondrial network. Gene transcript and protein content analysis of fission (e.g., Drp1) and fusion (e.g., Mfn1) proteins can infer active regulation of the mitochondrial reticulum, whereas advance microscopy techniques relying on fluorescent protein expression or auto-fluorescence can be used to visualize mitochondrial network connectivity (7). Mitochondrial content in skeletal muscle can be determined by citrate synthase enzyme activity, electron microscopy, and analysis of autophagy-related protein expression (e.g., LC3), or less reliably by mtDNA copies (8). Next, we summarize pathological mechanisms of various muscle stressors and highlight changes in the above outcome measurements (Table 1) to demonstrate the responsiveness of mitochondria to both physiological and pathological stimuli.

Table 1.

Mitochondrial sensitivity to skeletal muscle pathology: the impact of skeletal muscle injury and disuse on mitochondrial content, structure, and function, specifically during the acute stage of pathophysiology which differs by type, but ranges from immediate (e.g., VML) to 1 mo (e.g., disuse atrophy)

Skeletal Muscle Pathology	Impact on Mitochondrial Health
	Content	Structure	Function
Contraction-Induced	↓ or no Δ CS activity (9, 10) No Δ protein content (ETC) (9) ↑ autophagy (Beclin1) (10)	↓ fusion (Mfn2) (9) ↑ fission (Drp1) (9)	No Δ respiration (10) ↓ Δψ (11)a
IR	↓ protein content (e.g., cytochrome C) (12) ↑ autophagy (e.g., Beclin1, LC3, Ulk1) (12)	Unclear	↓ respiration (13) ↑ ROS (13)
Myotoxic	↓ or no Δ CS activity (14, 15) ↓ protein content (e.g., cytochrome C) (12, 14) ↑ autophagy (e.g., Beclin1, LC3, Ulk1) (12, 14)	↓ network organization (qualitative confocal) (12)	↓ respiration (14, 15) ↓ enzyme kinetics (complex I) (14)
Freeze	↓ CS activity (10, 16) ↑ autophagy (Beclin1, LC3) (10)	↑ fission (Fis1) (10, 16)	↓ respiration (10)
VML	↓ or no Δ CS activity (17, 18)	↓ network organization (quantitative multiphoton) (17, 19)	↓ respiration (17, 18)
Disuse Atrophy	↓ protein content (complex I & II) (20, 21) ↓ gene expression (e.g., complex I) (22) ↑ autophagy (LC3) (23)	↓ fusion (Mfn1) (23) ↓ fission (Fis1) (23)	↓ respiration (20, 21) ↑ ROS (20, 21)
Burn	↓ CS activity (24)	Unclear	↑↓ respiration (24)b ↓ Δψ (19) ↑ ROS (19)

CS, citrate synthase; ETC, electron transport chain; Mfn2, mitofusin-2 protein; Drp1, dynamin-related protein 1; Δψ, mitochondrial membrane potential; ROS, reactive oxygen species; LC3, microtubule-associated protein light chain 3; Ulk1, unc51-like kinase1; Fis1, mitochondrial fission 1 protein.

^aTransient response only detected immediately after injury.

^bRespiration normalized to mitochondrial content is greater, and unadjusted respiration is less.

Skeletal Muscle Injury and Disuse Influence Mitochondrial Networks

Individual muscle stressors are unique, although there are some overlapping cellular perturbations capable of influencing mitochondria. Muscle stressors that compromise sarcolemmal integrity (e.g., volumetric muscle loss injury) disrupt intracellular calcium homeostasis. Although aberrant intracellular Ca²⁺ levels temporarily aid clearing of postinjury debris, mitochondria initiate a non-bioenergetic role to uptake excess Ca²⁺ in attempt to regulate local calcium levels. This response can influence Δψ through opening of the mitochondrial permeability transition pore (mPTP). Two potential consequences of mPTP opening are reduced mitochondrial respiratory capacity and greater ROS production. Timely ROS production can facilitate muscle repair and improve muscle contractility; however, systemic or chronic oxidative stress is deleterious (25) and capable of initiating mitochondrial quality control mechanisms like mitochondrial fission and disposal via proteolysis and autophagy.

Contraction-Induced Injury

Contraction-induced injury, such as eccentric contractions performed during downhill running, results in immediate loss of muscle strength and greater susceptibility to calcium-induced mPTP opening (11). Acute changes in mitochondrial dynamics (9), decreased membrane potential (11), and increased autophagy-related protein expression (i.e., Beclin1) (10) were noted following injury. The extent to which mitochondrial content (e.g., CS activity) and function (e.g., respiration) are affected is unclear due to insufficient or contradictory evidence in the literature (9–11).

Ischemia Reperfusion Injury

Ischemia reperfusion (IR) injury, such as occurring with peripheral artery disease, is known to cause skeletal muscle mitochondrial dysfunction in both humans and animals across varied time points, even after just 5 min of reperfusion. Increased oxidative stress and mPTP opening are hallmarks of IR-mediated mitochondrial dysfunction as ischemia depletes ATP stores and oxygen access required for the electron transport chain. Reperfusion then perpetuates the damage via mitochondrial Ca²⁺ overload and increased ROS production (13). Increased mitochondrial release of cytochrome C and enhanced autophagy capacity occur between 2 and 14 days after injury (12).

Myotoxic and Freeze Injuries

Myotoxic (cardiotoxin, bupivacaine, barium chloride) and freeze injuries (used to investigate skeletal muscle regenerative capacity) involve rapid degeneration of myofibers and destruction of the mitochondrial network (10, 12, 14, 16) accompanied by marked decline in mitochondrial respiration (10, 14, 15). However, deficits in mitochondrial content and structure are transient, as network expansion and reorganization following injury can be visualized 5–10 days postinjury (12, 15). Robust upregulation of autophagy is evident by 28-fold and 9-fold increased autophagy-related protein Beclin1 expression following freeze (10) and cardiotoxin (12) injuries, respectively.

Volumetric Muscle Loss Injury

Although the aforementioned injuries in rodents generally recover in 4–6 wk, volumetric muscle loss (VML) injury ensues lifelong disability due to gross impairment of muscle function from limited endogenous myofiber regeneration (2). Percent reductions in contractile and metabolic function are greater than those predicted simply by the percent reduction in muscle mass (17), although the pathological mechanisms of metabolic dysfunction in particular are unclear. VML injury results in acute and persistence loss of mitochondrial respiratory capacity, independent of content (18), and widespread changes in mitochondrial structure (17, 26).

Disuse Atrophy

The unprecedented health crisis resulting in ICU-associated sedentarism and subsequent muscle wasting for patients with severe COVID-19 is a unique physiological challenge. Disuse atrophy studies (e.g., bed rest in humans and denervation in rodents) model this process while eliminating comorbidities as a confounder. Loss of constant mechanical stimuli required for muscle anabolism upregulates oxidative stress and AMPK/FOX03 pathway signaling characterized by muscle wasting and strength loss (20). Although muscle disuse studies are fairly inconsistent due to small sample size, young and old age groups display proportional decreases in mitochondrial content and oxidative capacity following 3 days to 3 wk of immobilization as well as elevated ROS emission (20, 21). Dirks et al. (21) suggest rapid post-translational modification of the ETC is initially responsible for impaired mitochondrial respiration, although autophagy likely contributes at a later time point. Experimentally, mitochondrial respiration decline precedes content (21), perhaps due to the estimated 14-day half-life of mitochondrial proteins. Gene expression analyses following atrophy indicate significant downregulation of 34 metabolic pathways associated with mitochondrial respiration (22) as well as altered mitochondrial dynamics (increased autophagy, decreased fission and fusion), which likely influence function (23).

Burn Injury

Mitochondrial dysfunction, loss of mass and strength, and systemic metabolic disruptions follow burn trauma. After noting diminished mitochondrial content and function at 7 and 21 days postburn (24), Porter et al. (19) investigated intramuscular mitochondrial function local and distal to the burn site, finding an acute apoptotic response versus a thermogenic phenotype characterized by severe uncoupling and chronic reduction in mitochondrial respiration, respectively. Systemic elevation of inflammatory cytokines and local ion imbalances from compromised cell membranes after burn injury likely contribute to mitochondrial dysfunction due to mPTP opening, loss of Δψ, and increased ROS production. These changes can persist as a hypermetabolic stress response for up to 2 yr postburn (19).

There is overwhelming evidence of mitochondrial content, structure, and function changes in response to various physiological and pathological stimuli. Experimental evidence indicates mitochondria are essential to the subsequent muscle regeneration as myoblasts fail to differentiate upon mtDNA and mitochondrial protein blocking, myotubes halt formation upon mtRNA blocking, and myoblasts wane proliferation upon mitochondrial protein synthesis blocking (16). Next, we summarize ways in which mitochondria respond to damage as potential molecular mechanisms of crosstalk with the inflammatory process.

MITO-DAMPS: SIGNALS THAT RESPOND TO STRESSORS

Following injury or stress, mitochondria release mito-DAMPs that are recognized by the innate immune system and trigger an inflammatory response in the local environment. Mitochondrial dysfunction associated with excess mito-DAMP release (e.g., ROS) exacerbates inflammation and can be detrimental to muscle homeostasis for functional recovery. A growing body of the literature proposes these danger signals all converge on a common pathway to activate the NLRP3 inflammasome in order to propagate inflammatory signaling via caspase-1-dependent secretion of pro-inflammatory cytokines IL-18 and IL-1β (4, 29). Although numerous intricacies remain unclear, the following highlights how individual mito-DAMP release potentiates inflammatory processes in the microenvironment which can impact skeletal muscle recovery outcomes.

ROS and Cardiolipin

Bouts of ROS emission in striated muscle are normal. For example, muscle contractility, such as during exercise, is associated with a greater ROS emission from both mitochondrial and nonmitochondrial [i.e., NAD(P)H oxidase] sources (27). This ROS production is an important contributor to contractile function and antioxidant gene responses; however, persistent or widespread oxidative stress is maladaptive and ensues deleterious cumulative damages (28). For example, blockage of mitochondrial disposal (autophagy) leads to an accumulation of damaged, ROS-generating mitochondria, and NLRP3/caspase-1/IL-1β inflammatory signaling axis activation (29). ROS also triggers cardiolipin translocation to the cytosol-facing outer membrane for NLRP3 recruitment and potentiation of immunogenic activity. As a mitochondrial-specific inner phospholipid, cardiolipin is necessary and sufficient for NLRP3 colocalization to the mitochondria (30). NLRP3 and caspase-1 each require cardiolipin for inflammasome assembly and cytokine autocatalysis activation (31), and mitochondria-generated ROS for membrane docking and activation (29, 31). Taken together, ROS is highly suspected as the upstream mediator of NLRP3 inflammasome activation (30, 31). Considering mitochondria are a main intracellular source of ROS (along with NAD(P)H oxidase) (27), upregulated oxidative stress following pathological muscle stimuli is an important contributor to NLRP-3-mediated inflammation (4).

mtDNA

Release of mtDNA upon mPTP opening triggers proinflammatory and type I interferon immune responses in vivo, likely due to evolutionarily conserved similarities to bacterial DNA including circularity and nonmethylated CpG motifs (5). mtDNA is certainly released into circulation upon skeletal muscle injury, as plasma levels in trauma patients measured several thousand times higher than normal (5). Notably, mtDNA directly activates the NLRP3 inflammasome and IL-1β production (3). In addition to mtDNA, mitochondrial N-formyl peptides (NFPs) are mito-DAMPs found at high levels in the circulation of trauma patients (4), which bind to high affinity formyl peptide receptors (FPRs) and attract neutrophils (5).

Cytochrome C

Although cytosolic release of cytochrome C activates an apoptotic signaling pathway (i.e., noninflammatory), extracellular release functions as a mito-DAMP in response to mPTP opening and mitochondrial damage (3). Interestingly, both processes require ROS, but the delineation of mitochondrial-induced apoptosome and inflammasome formation pathways remains unclear (29).

ATP

Extracellular release of ATP is multifunctional. Immunomodulatory-wise, ATP release from secondary necrotic cells and some types of accidental necrosis activates the NLRP3/caspase-1/IL-1β inflammatory pathway required for cytotoxic T-cell response and results in circulating neutrophil adherence at injury foci (4). Intracellular perturbations to the ATP/ADP ratio are likely further exacerbated by mitochondrial dysfunction, thereby activating master regulator AMPK pathway, which is similarly induced upon muscle disuse atrophy (3).

MITOCHONDRIA-CYTOKINE CROSSTALK FOLLOWING SKELETAL MUSCLE INJURY AND DISUSE

Inflammation following muscle injury requires robust homeostatic regulation as perturbation of the repair site can derail myogenesis. Given the role of mito-DAMPs in NLRP3 activation, mitochondrial signaling following muscle stress could be one of the earliest initiators of this process. Neutrophil infiltration to remove damaged fibers begins 1–3 h after injury, followed by a proinflammatory M1 macrophage phase (i.e., IL-1β, IFN-γ, ROS) supporting phagocytosis, immune cell recruitment, and myoblast proliferation. Under normal conditions, M1 levels decline by 48 h after injury as rising IL-10 and IL-Ra levels promote an anti-inflammatory M2 macrophage phase characterized by myoblast differentiation, suppression of local inflammation, and myogenesis promotion (32). Although transient upregulation of pro-inflammatory cytokines ameliorates muscle regeneration, prolonged pro-inflammatory presence quickly turns pathogenic. Failure to timely shift toward the anti-inflammatory M2 phase triggers muscle atrophy and limits repair to damaged tissues, as exhibited by burn injury (32).

Mito-DAMPs potentiate a chronic inflammatory response including aberrant cytokine release at the site of injury. Proper modulation of mitochondrial dynamics and/or cytokine release for optimal muscle recovery and regeneration remains unknown. Further investigation into specific cytokines which influence regenerative behavior following skeletal muscle injury and disuse is critical for the advancement of potential mitochondrial- and cytokine-targeted therapies. Here, we provide evidence on 4 cytokines—interleukin-6 (IL-6), interleukin-1β (IL-1β), chemokine C-X-C motif ligand 1 (CXCL1), and monocyte chemoattractant protein 1 (MCP-1)—which each were significantly upregulated upon gene expression meta-analysis following three unique muscle injury types (26, 33). Direct experimental evidence of cytokine regulation of mitochondrial networks, particularly in skeletal muscle, is limited. Muscle and nonmuscle studies are highlighted below. Overall, there is evidence that these cytokines modulate mitochondrial dynamics and execute bona fide pleiotropic roles, which could potentially aid functional recovery of muscle, however, when aberrant, chronically disrupt healing in part by exacerbating mitochondrial dysfunction (see Fig. 1). Further investigation is needed to delineate the opposing regulatory roles of inflammatory cytokines in the context of mitochondrial and muscle health.

Figure 1.

Positive feedback loop of mitochondrial stress following skeletal muscle pathology exacerbated by inflammation: Upon skeletal muscle injury or disuse, mitochondrial alterations occur which trigger release of mito-DAMPs. Chronic or aberrant downstream cytokine signaling (e.g., IL-6, IL-1β) can further potentiate mitochondrial stress and dysfunction, thereby preventing timely and complete functional recovery of skeletal muscle. CXCL1, chemokine C-X-C motif ligand 1; mito-DAMPS, mitochondrial-derived damage-associated molecular patterns; ROS, reactive oxygen species.

IL-6 Signaling in Skeletal Muscle

IL-6 is dual natured: Controlled levels are pro-myogenic, although systemic levels contribute to muscle atrophy and wasting. Specifically, acute IL-6 signaling through the JAK/STAT cascade is widely accepted to promote muscle hypertrophy and adaptation during regeneration via early macrophage invasion and myoblast proliferation (32), although chronic STAT3 activation accelerates muscle catabolism (34). Interestingly, permanent knockout of STAT3 in mdx mice also causes adverse effects (i.e., reduced satellite cell pool, aggravated fibrosis, muscle inflammation), although periodic STAT3 reduction via siRNA or pharmacological agent is beneficial for skeletal muscle repair (35). IL-6 is also a biomarker for adverse trauma outcomes (36), and IL-6 receptor blockade in vivo also improves mdx condition by promoting skeletal muscle regeneration (35). Conversely, IL-6 can be beneficial to skeletal muscle by providing energy through AMPK signaling to enhance glucose uptake, lipolysis, and fatty acid oxidation (35).

Regarding mitochondrial function, structure, and content, IL-6 supplementation increases mitochondrial respiration and ROS production in an IL6-receptor-α and STAT3-dependent mechanism in differentiating myotubes (37). Further, excess STAT3 mitochondrial import is postulated to promote ROS generation and ETC alterations (38). Fix et al. (34) also found mitochondrial fission 1 protein (Fis1) as an emerging IL-6-sensitive target in myotubes and skeletal muscle. Taken with previous work from this group demonstrating chronic IL-6 attenuates mitochondrial biogenesis and increases STAT3 and Fis1 in vivo and in vitro, IL-6 clearly disrupts mitochondrial quality via aberrant fission (34). Classic (membrane bound) versus trans (soluble) IL-6 receptor signaling may be the source of the functional dichotomy regarding IL-6 and the balance of inflammation and muscle fiber size. Importantly, IL-6 trans-signaling was recently identified to induce myotube autophagy and potentially mitochondrial disposal (35).

Although the IL-6 and skeletal muscle mitochondrial narrative is still developing, TNF-α and IL-1β are known to activate IL-6 largely through NFκB, suggesting a positive feedback loop exists among infiltrating cells and muscle to elevate IL-6 levels around the foci of injury (39). Mito-DAMPs may be capable of initiating this pathway as stimulation of mouse splenocytes with cytochrome C in vitro activated NFκB/TNF/IL-6 and MCP-1 (4). In regard to cytokine therapeutics following skeletal muscle stressors, administration of melittin, and a component of bee venom, following muscle injury attenuates MCP-1 plasma levels as well as TNF-α and IL-6 levels at the foci of damage associated with concurrent upregulation of myofibril regeneration biomarkers and improved morphological recovery (40).

IL-1β/CXCL1 Signaling in Skeletal Muscle

To phagocytose necrotic debris, IL-1β is secreted by M1 macrophages during the pro-inflammatory phase after injury and is later inhibited by rising IL-Ra levels during the anti-inflammatory M2 macrophage stage. Perhaps, IL-1β directly interacts with the mitochondria via the NLRP3/caspase-1/IL-1β signaling axis. Indeed, hypersecretion of IL-1β, mimicked via isoprenoid-deficient monocytes, demonstrates increased Δψ as well as reduced mitochondrial stability, autophagy, and antioxidant capacity (41). Consistent with these findings, IL-1β induces mitochondrial fragmentation, impairs respiration via a fission protein in astrocytes (42), and impairs complex I activity in chondrocytes (43). Further, IL-1β-treated retinal neuron cells experience intracellular ATP depletion, ROS generation, and attenuated Δψ (44). Taken together, IL-1β exacerbates a loop of inflammation and potentiates mitochondrial dysfunction in vitro.

CXCL1 is known to be involved in neutrophil and M2 phenotype macrophage recruitment for wound healing in skeletal muscle but paradoxically was found to antagonize myogenesis and disrupt myofiber satellite cell homeostasis in vivo and in vitro (45). Although the manner by which CXCL1 modulates myogenesis remains unclear, models of acute arthritis (46) and dermatitis (47) have found IL-1β to induce production of CXC chemokines, including CXCL1. This suggests the existence of an IL-1β/CXCL1/2/neutrophil axis responsible for a potential feedforward relationship, evidenced by IL-1β-deficient mice, which have severely deficient CXCL1/2 production and neutrophil levels. Findings of highly correlated levels of CXCL1 and IL-1β after three distinct muscle injuries (1, 26) support a potential for this signaling axis in skeletal muscle, although experimental evidence of effects on mitochondrial networks is needed.

MCP-1 Signaling in Skeletal Muscle

Monocyte chemoattractant protein 1 (MCP-1) is secreted by damaged myofibers, resident macrophages, and activated satellite cells to initiate extravasation of monocytes to sites of inflammation and subsequent differentiation into macrophages. MCP-1 release appears beneficial following acute skeletal muscle injury as pathway blockade (i.e., MCP-1 pharmacological inhibition or receptor knockout) delays strength recovery after freeze injury (48) and reduces macrophage infiltration and myotube formation after ischemic and myotoxic injuries (49). Excessive MCP-1 is known to be pathogenic, is found across a host of chronic inflammatory disorders (49), and ensues direct mitochondrial damage including cytochrome C release as well as attenuated transmembrane potential upon administration on HUVECs in vitro (50). Notably, a vascular inflammation study found MCP-1 involved in the stress-induced IL-6-positive feedback loop (36). In the context of skeletal muscle, this is a potential mechanism for exacerbating mitochondrial dysfunction and prolonging recovery from injury.

CONCLUSIONS

In this mini-review, we outline how mitochondrial content, structure, and function are disrupted following skeletal muscle injury and disuse and then highlight the role of mitochondria-cytokine crosstalk in functional muscle recovery. Although acute homeostatic imbalances (e.g., ROS generation, inflammation) are necessary and beneficial following muscle stressors, exhaustive signaling associated with dysfunctional mitochondria is detrimental to skeletal muscle health. Excess mito-DAMPs propagate pro-inflammatory processes via aberrant, chronic cytokine release at the site of injury which impedes functional muscle recovery. Future directions need to explore mitochondria-cytokine crosstalk further to accelerate skeletal muscle recovery after injury and disuse.

GRANTS

We acknowledge the Winston Churchill Foundation of the United States, the Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense, through the Clinical & Rehabilitative Medicine Research Program, FY17 Neuromusculoskeletal Injuries Rehabilitation Research Award (W81XWH-18-1-0710 to J. A. C.), and the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development (I21 RX003188).

DISCLAIMERS

Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense, the Department of Veterans Affairs, or the US Government.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

A.E.Q. prepared figure; A.E.Q. drafted manuscript; A.E.Q., W.M.S., and J.A.C. edited and revised manuscript; A.E.Q., W.M.S., and J.A.C. approved final version of manuscript.