Muscle atrophy – the gradual loss of muscle mass – follows injuries to our muscles, tendons, or joints. During atrophy, muscles shrink and become weaker, which can interfere with everyday activities and, ultimately, decrease quality of life.

Rotator cuff tears are a common example of such injuries. A rotator cuff is group of four muscles that come together as tendons to form a cuff that normally stabilises our shoulders and allows us to lift and move our arms over our heads. Rotator cuff tears can result from an injury or may be caused by ageing-related wear and tear of the tendon.

A signalling protein, called NFκB, is thought to be involved in muscle atrophy. When the NFκB signal is switched on, it interacts with genes that are thought to speed up the loss of muscle mass. However, NFκB’s precise role in atrophy and recovery after muscle injury is still poorly understood, particularly following injuries where a tendon is cut or torn. Meyer et al. therefore set out to determine whether or not NFκB played a role in the muscle atrophy following rotator cuff tears.

Meyer et al. used genetically engineered mice in which NFκB’s signal could be turned off at the time of rotator cuff injury, and specifically in muscle cells (but not other parts of the body). The experiments revealed that stopping NFκβ signalling in these mice did not reduce muscle atrophy after a rotator cuff injury: the levels of atrophy, muscle performance, and muscle composition were the same regardless of whether the NFκβ signal was active.

The sex of the mice did, however, affect muscle atrophy, specifically the way in which they lost muscle mass. In male mice, the size of muscle cells decreased, while in female mice, the number of muscle cells decreased. Muscle cells in male mice (but not in females) also accumulated abnormally high amounts of protein, which is an indication of a mechanism of muscle breakdown called autophagy.

These results shed new light on the way that we lose muscle mass after injury, and how that could vary depending on the individual. Meyer et al. hope that this study will help guide the development of new, more effective treatments for muscle atrophy, and ultimately contribute to therapies tailored to the characteristics of the patient and the type of injury.

At the most basic level, skeletal muscle atrophy is a shift in the physiological balance between protein synthesis and breakdown. This shift can be initiated by a wide variety of stimuli, from disuse to starvation to cancer, but all eventually converge on a common result – reduced muscle mass. As expected from the diverse stimuli, atrophy can be initiated through a variety of intracellular pathways. However, studies have found surprising commonality downstream, leading to the identification of a number of ‘lynchpin’ mediators – in particular signaling through nuclear factor kappa beta (NFκB), which has been described as both necessary and sufficient for skeletal muscle atrophy (Jackman et al., 2013; Sandri, 2013).

Our current understanding of NFκB’s role in adult muscle atrophy has been reviewed in detail (Jackman et al., 2013), where the reader can find illustrations of the pathway. In brief, NFκB is a family of transcription factor subunits that exist as dimers and are localized to the cytoplasm by inhibitory kinases (inhibitor of κB, IκB). Upon stimulation, IκB kinases (IKKα and IKKβ) are phosphorylated and in turn phosphorylate IκB (predominantly IκBα). This leads to cytosolic degradation of Iκβ and nuclear transport of NFκB transcription factor dimers to initiate transcription of genes involved in the atrophy program. Inhibiting IKKβ activity by muscle-specific knockout of its gene (Ikbkb) or electroporating a dominant negative form into skeletal muscle prevented approximately half the loss of muscle mass induced by denervation (Mourkioti et al., 2006), unloading (Van Gammeren et al., 2009), or immobilization (Reed et al., 2011). Similar results were found in the Iκβα superrepressor mouse, which displays dampened NFkB activity, in response to an inflammatory insult (Haegens et al., 2012; Langen et al., 2012) denervation (Cai et al., 2004), unloading (Judge et al., 2007), nutrient deprivation (Lee and Goldberg, 2015), or tumor (Cai et al., 2004). Assessment of NFκB activity by nuclear localization or DNA binding of its subunits confirmed that inhibition of IKKβ activity or IκBα degradation completely (Cai et al., 2004; Senf et al., 2008; Van Gammeren et al., 2009) or partially (Mourkioti et al., 2006) blocked NFκB translocation, demonstrating that NFκB signaling is responsible for a considerable portion of atrophy driven by these diverse stimuli.

The best-studied gene targets of NFκB in muscle are the E3 ubiquitin ligases muscle ring finger 1 (MuRF1) and muscle atrophy F-box (MAFbx; a.k.a. Atrogin-1). These genes, termed ‘atrogenes,’ are thought to control the majority of proteolysis in skeletal muscle across atrophic conditions (Bodine et al., 2001; Gomes et al., 2001). Knockout of MuRF1 results in a similar extent of muscle sparing to NFκB inhibition in denervation (Gomes et al., 2012), unloading (Labeit et al., 2010), glucocorticoid treatment (Baehr et al., 2011), and inflammatory insult (Files et al., 2012), leading it, too, to be labeled ‘essential’ for skeletal muscle atrophy (Peris-Moreno et al., 2020). While compelling, this explanation remains incomplete. First, because inhibition of NFκB or MuRF1 signaling does not completely prevent atrophy induced by these various stimuli and second because the degree of prevention varies by stimulus and muscle. For example, muscle-specific Ikbkb knockout prevented ~70% of denervation-induced decrease in mass of the soleus muscle, but only ~30% in the gastrocnemius muscle (Mourkioti et al., 2006). Similarly, Iκβα super-repressor prevented only ~25% of the denervation-induced mass loss in the gastrocnemius and tibialis anterior muscles but ~50% of the tumor-induced loss in mass (Cai et al., 2004).

Recently, tendon tears (leading to release of muscle tension and muscle retraction) have emerged as potentially employing distinctive mechanisms of muscle atrophy. A comparative study of atrophic signaling between tenotomy and immobilization found that tenotomized gastrocnemius muscle atrophy was primarily characterized by a lysosomal/autophagic signature, in contrast to the classical ubiquitin-mediated proteasomal activity signature of the immobilized gastroc (Bialek et al., 2011). MuRF1 or MAFbx expression did not significantly increase with tenotomy, where dramatic increases were again shown with immobilization, denervation, and glucocorticoid-induced atrophy. This is somewhat surprising given the similarity in signaling induced by other models of unloading that remove either passive loading (e.g., hindlimb suspension and immobilization by casting) or active loading (e.g., denervation). In fact, previous to this study, tenotomy was assumed to employ the ubiquitin-mediated proteasome activity through NFκB and the atrogenes simply because of this similarity (Laron et al., 2012). More recent studies have focused on tenotomy of the rotator cuff (RC) muscles (without suprascapular nerve injury) as a model to investigate the mechanisms of muscle atrophy in human chronic RC tears. These studies have confirmed no increases in MuRF1 or MAFbx following RC tenotomy (Liu et al., 2012) and have uncovered additional evidence for increased autophagic flux (Gumucio et al., 2012; Joshi et al., 2014). Evidence in support of proteasomal activity in the early phase of RC tenotomy, however, also exists (Valencia et al., 2017), leaving open the possibility of coordinated action of multiple pathways.

Taken together, these prior studies suggest that although NFκB signaling is a critical component of many disparate atrophy models, it may not be ubiquitous – and in particular may not play a major role in tenotomy-induced atrophy. However, due to the complexity of NFκB signaling, its role in tenotomy-induced atrophy (or lack thereof) cannot be inferred from the lack of atrogene expression or the autophagic state of the muscle alone. First, because evidence suggests that NFκB is capable of driving atrophy independent of MuRF1 or MAFbx (Cai et al., 2004) and second, because there is a complex link between NFκB and autophagy which could cause NFκB to drive the autophagic process (reviewed in Xia et al., 2021). In this study, we sought to determine the role of NFκB signaling in tenotomy-induced atrophy of the RC muscles using muscle-specific gain- and loss-of-function IKKβ transgenic mouse models to inhibit and promote NFκB activity, respectively. We hypothesized that NFκB inhibition would ameliorate tenotomy-induced atrophy through an atrogene-independent mechanism, thus supporting NFκB inhibitors as a novel therapeutic strategy to maintain muscle mass following human chronic RC tears. However, we found that knockdown of IKKβ had no impact on the loss of muscle mass or contractile performance following tenotomy and that overexpression of constitutively active IKKβ was insufficient to drive muscle atrophy. Instead, our data point to an NFκB-independent, sex-specific mechanism driven by autophagy.

This study investigated the effects of NFκB inhibition on muscle atrophy following tenotomy. Using a transgenic muscle-specific and inducible deletion of IKKβ, we were able to block more than 50% of the nuclear translocation of NFκB subunits in muscle fibers at the time of tenotomy of the RC muscles. While this caused a mild increase in muscle mass in general, it surprisingly had no additional effect on any outcomes following tenotomy, including muscle mass and contractile force, fiber area, length and number, and atrophic signaling through the ubiquitin-proteasome and autophagy pathways. Similarly, doubling IKKβ expression using a gain-of-function mouse model had little effect on muscle responses to tenotomy. Together, these results indicate that NFκB does not play a major role in mediating tenotomy-induced atrophy. Interestingly, this study also uncovered sex-specific mechanisms of tenotomy-induced atrophy, most evident at the later timepoints investigated. Male, but not female, mice continued to lose muscle mass between 2W and 8W post-tenotomy. The sex-specific result was likely due to ongoing type 2b fiber atrophy driven by accumulation of autophagic vesicles, which was exacerbated in males at 8W. This surprising finding warrants further investigation in naïve wildtype mice.

The finding that IKKβ knockdown had little effect on tenotomy-induced muscle atrophy aligns with the limited data in tenotomy models, but is contrary to the NFκB muscle atrophy dogma. Transgenic interference with NFκB signaling substantially reduced loss of muscle mass across nearly every model investigated, including unloading, immobilization, denervation, acute inflammatory challenge, nutrient deprivation, and cancer (Cai et al., 2004; Mourkioti et al., 2006; Judge et al., 2007; Van Gammeren et al., 2009; Reed et al., 2011; Haegens et al., 2012; Langen et al., 2012; Lee and Goldberg, 2015). These models encompass diverse stimuli for atrophy that are frequently subcategorized as disuse, aging, or disease (Romanick et al., 2013). Tenotomy is typically included in the disuse category, along with unloading, immobilization, and denervation. However, tenotomy is fundamentally unique in that it severs the connection of the muscle to the skeleton, eliminating passive tension and immediately changing the length of the muscle as the muscle recoils and comes to rest in a shortened position. Importantly, tenotomy alone does not involve any direct damage to the muscle or its innervation, avoiding confounding effects of denervation and extensive regeneration. While RC tenotomy is frequently paired with denervation to elicit more dramatic muscle pathology (particularly fatty infiltration), there is not strong evidence that nerve damage is a consistent feature of even massive RC tears in humans (Costouros et al., 2007). Similarly, extensive regeneration does not appear to be a notable feature of RC tears in humans, where only ~10% of fibers exhibit central nucleation, compared with ~3% in controls (Gibbons et al., 2017). In the mouse, we find no proliferation of satellite cells at W1 following tenotomy and only a minor (<3%) increase in centrally nucleated fibers at later timepoints. This, combined with the lack of dilution of the NFkb knockdown at the gene and protein level, suggests that the genetically unmodified SCs are not contributing substantial additional myonuclei. However, unlike human tears, rodent models of tenotomy develop a fibrous ‘pseudo-tendon’ scar in the gap between the tendon and bone, partially restoring passive loading to the muscle (Jamali et al., 2000). This retraction plus scarring in the shortened position induces the loss of muscle mass in the longitudinal dimension by sarcomere subtraction (Ward et al., 2010; Meyer, 2022); a phenomenon that does not occur in hindlimb unloading or denervation models and, to a lesser extent, in immobilization models (Heslinga and Huijing, 1993; Van Dyke et al., 2012). Tenotomy and immobilization are also the only disuse models to demonstrate central core lesions of myofibril breakdown, hypothesized to be due to contraction in the shortened position. However, these are also exacerbated in tenotomy compared with immobilization (Baewer et al., 2004; Baewer et al., 2008). This suggests that tenotomized muscle is engaged in high levels of active remodeling, differentiating it from models reducing excess muscle mass in response to decreased use. This active remodeling could be responsible for the unique degradation signature in tenotomy compared with immobilization or denervation (Bialek et al., 2011; Liu et al., 2012; Joshi et al., 2014), where either the myofibril breakdown or selective serial sarcomere subtraction is engaging autophagic mechanisms. Our data also suggest that the mechanisms of muscle loss may vary temporally following tenotomy. IKKβ knockdown had the greatest effect on tenotomized muscle mass at W1 (Figure 3A), which aligned with main the effects of treatment in ubiquitin protein abundance and MuRF1 expression (Figure 7A and B). These transient effects could be due to a differential atrophic responses of the muscle pre- and post-scarring or due to the resolution of inflammatory signals following tenotomy.

Interestingly, while male mice continued to lose muscle mass between W2 and W8 post-tenotomy, the contractile deficit stabilized (Figure 3). Peak tetanic tension is normalized to PCSA, which theoretically accounts for changes in fiber CSA/number and serial sarcomere subtraction, but even after this normalization, a deficit remained. The source of this deficit is unknown. It could be that PCSA is not fully accounting for the impact of morphological changes on contractile force or the deficit may be attributed to another factor, such as muscle quality. The fact that contractile properties remained stable during ongoing atrophy in male mice suggests that PCSA does sufficiently account for these changes. Additionally, data in the tenotomized rat SS indicate that contractile deficits precede morphological changes and are measurable as soon as 1 day post-tenotomy, remaining stable for 2 weeks (Valencia et al., 2017). This suggests that the contractile deficit originated early in the tenotomy injury and never resolved during the subsequent process of healing. There is considerable evidence for myofibrillar disruption and fiber damage post-tenotomy (reviewed in Jamali et al., 2000), and it is possible that the tenotomized muscle cannot adequately repair this damage in its unloaded state. If this is the case, it also offers an explanation for why IKKβ knockdown did not affect the contractile deficits. However, it is difficult to say whether some recovery of this initial damage occurs and is offset by the later development of structural pathology (e.g., fibrosis, fat infiltration, basophilic puncta, etc.) or whether the degree of this later structural pathology is insufficient to drive additional measurable contractile changes, as other work suggests it does (Biltz et al., 2020). Future studies using targeted mouse models such as the lipodystrophic mouse (that does not develop fat infiltration) or pharmacologics that target accumulation of autophagic vesicles could shed some light on this question.

Expression of a constitutively active form of IKKβ doubled the concentration of IKKβ in mice, yet this increase had negligible effects on tenotomy-induced atrophy. This finding is in contrast to findings from the MIKK mouse and transfection of constitutively active IKKβ, which reportedly induced significant muscle atrophy, even in the absence of an unloading stimulus (Cai et al., 2004; Van Gammeren et al., 2009). However, these studies notably induced more than tenfold increases in constitutively active IKKβ, levels that may be supra-physiological. Our findings suggest that smaller increases in IKKβ may not be sufficient to drive atrophy without an additional stimulus.

Increased protein ubiquitination has been observed early (2–15 days) post-tenotomy (Baewer et al., 2008; Valencia et al., 2017), which could indicate coordinated action of multiple activated pathways, one of which may be regulated by NFκB. Due to this mounting evidence for autophagy due to tenotomy, it was reasonable to hypothesize in this study that NFκB might also be involved in the atrophic process. Additionally, NFκB could directly affect autophagy as several autophagic regulatory genes (Beclin 1, Atg6, and LC3) are targets of NFκB in other tissues (Copetti et al., 2009; Nivon et al., 2009). While our data strongly suggest that NFκB does not play a major role in tenotomy-induced atrophy, there are several limitations that could have masked some NFκB-driven effects. First, HSA-driven deletion of Ikbkb was only 50–60% efficient, leaving 40–50% of the endogenous levels of IKKβ to participate in NFκB signaling. Indeed, we found 40–50% of endogenous WT NFκB subunits p50 and p65 present in the nuclear fraction. By comparison, constitutive deletion of Ikbkb under control of muscle creatine kinase (MCK) was 70% efficient (Mourkioti et al., 2006), and blocking IKKβ activity using the IKβα super-repressor mouse or transfection of dominant-negative IKKβ completely blocked NFκB nuclear translocation (Cai et al., 2004; Van Gammeren et al., 2009). The reasons for our limited efficacy are unclear, but may derive from the efficiency of tamoxifen, as ours was the only study to use an inducible transgenic model. However, our lesser impacts on the NFκB pathway are likely more translationally relevant as NFκB inhibitors have a comparable impact on the NFκB pathway as reported here (Belova et al., 2017) and have detrimental off-target effects at high doses (reviewed in Mourkioti and Rosenthal, 2008). Thus, while it is possible that residual activation of NFκB signaling is sufficient to drive tenotomy-induced atrophy in our model, our data still suggest that pharmacological inhibition of NFκB signaling is not likely to be therapeutically valuable. Furthermore, our findings in wildtype mice that IKKβ protein levels and nuclear NFκB subunits were unchanged by tenotomy provide additional evidence against NFκB driving tenotomy-induced muscle loss as both of these are increased in other models of unloading (Hunter et al., 2002; Van Gammeren et al., 2009). Furthermore, we also found only a very small increase in the major gene target of NFκB-induced atrophy (MuRF1) following tenotomy, consistent with other reports (Bialek et al., 2011; Liu et al., 2012).

Evidence for autophagy regulating tenotomy-induced atrophy has been mounting in recent years (Bialek et al., 2011; Gumucio et al., 2012; Joshi et al., 2014; Ning et al., 2015; Hirunsai and Srikuea, 2021). The evidence presented here supports this contention, but we find surprisingly small effect sizes for all markers investigated. This could be because we did not directly assess autophagic flux and so missed some temporal dynamics since synthesis and degradation are ongoing simultaneously. It could also be because autophagy is only one piece of a more complex atrophic regulation. Notably, Foxo3 regulates autophagy/lysosomal and ubiquitin/proteasomal degradation (Zhao et al., 2007), and this master regulator was not assessed in detail here. Additionally, a number of E3 ubiquitin ligases other than MuRF1 and MAFbx regulate muscle atrophy (Ye et al., 2007; Nagpal et al., 2012; Hindi et al., 2014). Thus, it is possible that NFκB-driven atrophy was affected by IKKβ knockdown, but compensation by another atrophic pathway obscured the effects on muscle mass etc. The complex interplay between these pathways warrants further investigation.

Few studies have investigated sex-specific effects in muscle atrophy, particularly in the context of tenotomy. Studies in other disuse models indicated that atrophy, and the pathways that modulate it, may vary by sex. Soleus atrophy during hindlimb unloading was exacerbated in female rats compared with male rats (Yoshihara et al., 2019; Rosa‐Caldwell et al., 2021; Yoshihara et al., 2022). This was associated with increased FoxO3a activity, protein ubiquitination, and myostatin expression in females compared to males, with no differences in autophagy or Akt phosphorylation (Yoshihara et al., 2019). In humans, females experience greater levels of atrophy in response to disuse and aging, while males have greater loss of muscle in response to cancer (reviewed in Rosa-Caldwell and Greene, 2019), suggesting that sex specificity extends to clinical populations as well. In the human RC, symptomatic tear development and progression are more prevalent in males (Yamamoto et al., 2017; Song et al., 2022). Here, we find that not only do male mice lose more mass after tenotomy, they lose it uniquely through type 2b fiber atrophy, while female mice lose mass uniquely through fiber hypoplasia. It is possible that both sexes experience some fiber degeneration (as has been noted in chronic human RC tears; Gibbons et al., 2017), but males are more efficiently repairing the damaged fibers; this speculation would explain the sex specificity in central nuclei, then the load borne by fewer fibers helps maintain fiber CSA. While these differences are relatively minor, they suggest that some sex specificity in chronic tear outcomes could be intrinsically biological or an interaction between intrinsically biological and behavioral factors. To further explore the clinical relevance of these findings, it will be important to determine whether these changes affect recovery of mass and function following surgical repair and rehabilitation. This would necessitate moving to a larger animal model, but would also afford the opportunity to explore whether this sex specificity is conserved between species.

The most dramatic difference we observed between males and females was the increase in basophilic puncta positive for autophagic vesicle markers p62 and LC3 in male muscles at W8 post-tenotomy compared with female muscles. This suggests that the ongoing mass loss concurrent with their appearance may be mediated by autophagy. However, we found only mild differences in LC3 protein content between male and female muscles at this timepoint. Thus, the issue in the male mice may be dysregulated autophagic flux with accumulation of large autophagic vesicles. Proper assessment of autophagic flux cannot be done on existing samples as it requires treatment of mice with lysomotropic agents prior to muscle harvest. Additionally, it is important to note that estrous cycle was not controlled in these mice and sex hormone levels were not measured in this study. These preliminary observations, though intriguing, will require more rigorous follow-up evaluations to define the interaction between sex, tenotomy, and autophagy in naïve wildtype mice.

In conclusion, we found that a twofold gain- or loss-of-function of IKKβ did not impact tenotomy-induced muscle atrophy or contractile dysfunction. This suggests that IKKβ/NFκB inhibitors are unlikely to improve muscle outcomes through direct inhibition of atrophy in human RC tears. Given promising preclinical data suggesting that IKKβ inhibitors improve tendon-to-bone healing after RC tenotomy and repair (Golman et al., 2021), and NFκB inhibitors improve muscle mass and contractile function in disease models (Messina et al., 2006), it was logical to hypothesize that they would also directly improve muscle outcomes in human rotator cuff disease. However, this hypothesis was not supported by our data, which suggest that tenotomy, and likely human RC tears, is a unique model of muscle atrophy driven by factors associated with the loss of muscle passive tension. It is important to note, however, that NFκB inhibitors still have the potential to improve muscle outcomes indirectly by targeting satellite cells, FAPs, and/or tenocytes, all of which will be involved in the development of pathology or the potential for rehabilitation and none of which were genetically modified in this study. Future work comparing these results with NFκB inhibitors could shed light on their therapeutic potential for preventing tenotomy-induced atrophy and the mechanisms of action. Intriguingly, our data also revealed a preliminary observation of sex specificity in the atrophic response following tenotomy that warrants further exploration. This aligns with sex specificity in human RC tears and could guide more effective and individualized therapies.

All data generated or analyzed during this study are included. Data files have been provided for all Figures.

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Author details

1. Gretchen A Meyer

   1. Program in Physical Therapy, Washington University School of Medicine, St. Louis, United States
   2. Department of Orthopaedic Surgery, Washington University School of Medicine, St Louis, United States
   3. Departments of Neurology and Biomedical Engineering, Washington University School of Medicine, St. Louis, United States

   Contribution

   Conceptualization, Resources, Data curation, Software, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   meyerg@wustl.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-9268-3993

2. Stavros Thomopoulos

   Departments of Orthopaedic Surgery and Biomedical Engineering, Columbia University, New York, United States

   Contribution

   Conceptualization, Funding acquisition, Project administration, Writing – review and editing

   Competing interests

   Reviewing editor, eLife

3. Yousef Abu-Amer

   1. Department of Orthopaedic Surgery, Washington University School of Medicine, St Louis, United States
   2. Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, United States
   3. Shriners Hospital for Children, St. Louis, United States

   Contribution

   Resources, Validation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5890-5086

4. Karen C Shen

   Program in Physical Therapy, Washington University School of Medicine, St. Louis, United States

   Contribution

   Data curation, Writing – review and editing

   Competing interests

   No competing interests declared

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