Pathophysiological changes of muscle after ischemic stroke: a secondary consequence of stroke injury

Abstract

Sufficient clinical evidence suggests that the damage caused by ischemic stroke to the body occurs not only in the acute phase but also during the recovery period, and that the latter has a greater impact on the long-term prognosis of the patient. However, current stroke studies have typically focused only on lesions in the central nervous system, ignoring secondary damage caused by this disease. Such a phenomenon arises from the slow progress of pathophysiological studies examining the central nervous system. Further, the appropriate therapeutic time window and benefits of thrombolytic therapy are still controversial, leading scholars to explore more pragmatic intervention strategies. As treatment measures targeting limb symptoms can greatly improve a patient's quality of life, they have become a critical intervention strategy. As the most vital component of the limbs, skeletal muscles have become potential points of concern. Despite this, to the best of our knowledge, there are no comprehensive reviews of pathophysiological changes and potential treatments for post-stroke skeletal muscle. The current review seeks to fill a gap in the current understanding of the pathological processes and mechanisms of muscle wasting atrophy, inflammation, neuroregeneration, mitochondrial changes, and nutritional dysregulation in stroke survivors. In addition, the challenges, as well as the optional solutions for individualized rehabilitation programs for stroke patients based on motor function are discussed.

Keywords: inflammation; ischemic stroke; mitochondria; muscle atrophy; muscle fiber; muscle nutrition; quality of life; rehabilitation; ubiquitin.

Figure 1

The causes of muscle atrophy after stroke. Primary causes of muscle atrophy after stroke are disuse atrophy, nerve regeneration, muscle inflammation, protein synthesis and catabolism, muscle fiber type transformation, muscle mitochondrial function changes, and nutrient supply. Created with Figdraw (www.figdraw.com). MHC: Major Histocompatibility complex; ROS: reactive oxygen species.

Figure 2

Ischemic stroke changes fiber size of skeletal muscle by regulating the synthesis and degradation system via NF-κB and FoxO signaling pathways. Inflammatory factors such as TNF-α and ROS activate the NF-κB pathway, inducing the expression of p50, bcl-3, and MMP-9 proteins, while inhibiting protein synthesis. Stroke injury factors also activate the ubiquitination system through the AMPK pathway, leading to muscle degradation. IGF-1 can activate the AKT/PI3K/mTOR pathway, and promote the expression of key factors, such as p70, 4E-BP1, and eIF4G1 to stimulate muscle protein synthesis. Created with Figdraw (www.figdraw.com). 4E-BP1: Eukaryotic translation initiation factor 4E binding protein 1; AKT: protein kinase B; AMPK: AMP-activated protein kinase; Atrogin-1: F-box protein 32; Bcl-3: B-cell lymphoma-3; Bnip3: BCL2/adenovirus E1B 19kDa interacting protein 3; eIF3f: eukaryotic initiation factor 3; eIF4G1: eukaryotic translation initiation factor 4 gamma 1; FoxO: forkhead box-O; IGF-1: insulin-like growth factor-1; LC3B: microtubule-associated protein-1 light chain-3 beta; MMP-9: matrix metallopeptidase 9; Mtor: mammalian target of rapamycin; mTORC1: mechanistic target of rapamycin complex 1; MuRF-1: tripartite motif-containing 63; MyoD: myogenic differentiation; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B-cells; p50: nuclear factor of kappa light polypeptide gene enhancer in B-cells 1; p70: p70 S6 kinase; PGC-1α: peroxisome proliferator-activated receptor gamma, coactivator-1 alpha; PI3K: phosphatidylinositol-3 kinase; ROS: reactive oxygen species; TNF-α: tumor necrosis factor.

Figure 3

Mitochondrial related apoptosis leading to post-stroke muscle atrophy. Exogenous Inflammatory factors (such as TNF-α and ROS) up-regulate the expression of apoptotic proteins (caspase-3, caspase-6, and caspase-8) and trigger the inflammation process in skeletal muscle. Then, end products of the activated NF-κB pathway further induce mitochondrial apoptosis, leading to the degradation of muscle proteins. Additionally, activation of the AKT pathway inhibits cytochrome c release and increases protein synthesis. Created with Figdraw (www.figdraw.com). AKT: Protein kinase B; Atg7: autophagy-related protein-7; Bcl-2: b-cell lymphoma-2; Bcl-XL: b-cell lymphoma extra-long; Bak: BCL2 antagonist kinase; Bax: BCL2-associated X; caspase-3: apoptosis-related cysteine peptidase-3; caspase-6: apoptosis-related cysteine peptidase-6; caspase-8: apoptosis-related cysteine peptidase-8; caspase-9: apoptosis-related cysteine peptidase-9; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K: phosphoinositide 3-kinase; ROS: reactive oxygen species; TNF-α: tumor necrosis factor-alpha.